US20080188557A1 - Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof - Google Patents
Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof Download PDFInfo
- Publication number
- US20080188557A1 US20080188557A1 US12/008,124 US812408A US2008188557A1 US 20080188557 A1 US20080188557 A1 US 20080188557A1 US 812408 A US812408 A US 812408A US 2008188557 A1 US2008188557 A1 US 2008188557A1
- Authority
- US
- United States
- Prior art keywords
- compound according
- cancer
- group
- pharmaceutically acceptable
- acceptable carrier
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 272
- -1 (substituted phenyl)-propenal moiety Chemical group 0.000 title abstract description 56
- 230000004071 biological effect Effects 0.000 title description 12
- 239000003098 androgen Substances 0.000 claims abstract description 37
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 27
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 27
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims abstract description 21
- 206010068597 Bulbospinal muscular atrophy congenital Diseases 0.000 claims abstract description 16
- 208000027747 Kennedy disease Diseases 0.000 claims abstract description 16
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 9
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 9
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 9
- 201000007270 liver cancer Diseases 0.000 claims abstract description 9
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 9
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 9
- 201000004384 Alopecia Diseases 0.000 claims abstract description 8
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 5
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 206010000496 acne Diseases 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- 231100000360 alopecia Toxicity 0.000 claims abstract description 4
- 206010020112 Hirsutism Diseases 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims description 91
- 238000000034 method Methods 0.000 claims description 49
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 29
- 239000003937 drug carrier Substances 0.000 claims description 28
- 201000011510 cancer Diseases 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical group CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 3
- 125000005594 diketone group Chemical group 0.000 claims description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical group CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 52
- 238000011282 treatment Methods 0.000 abstract description 25
- 239000002537 cosmetic Substances 0.000 abstract description 15
- 230000002265 prevention Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 206010052428 Wound Diseases 0.000 abstract description 2
- 208000027418 Wounds and injury Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- 102100032187 Androgen receptor Human genes 0.000 description 62
- 108010080146 androgen receptors Proteins 0.000 description 60
- 210000004027 cell Anatomy 0.000 description 47
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 230000000694 effects Effects 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- ZMGUKFHHNQMKJI-CIOHCNBKSA-N (1e,4z,6e)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(\O)=C\C(=O)\C=C\C1=CC=C(OC)C(OC)=C1 ZMGUKFHHNQMKJI-CIOHCNBKSA-N 0.000 description 30
- 239000000178 monomer Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 0 [3*]C1=C([4*])C=CC(/C=C/C(C)=O)=C1 Chemical compound [3*]C1=C([4*])C=CC(/C=C/C(C)=O)=C1 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- 108090000623 proteins and genes Proteins 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 12
- 238000001262 western blot Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 102000005969 steroid hormone receptors Human genes 0.000 description 11
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical class CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 10
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 108010029485 Protein Isoforms Proteins 0.000 description 9
- 102000001708 Protein Isoforms Human genes 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 108010085012 Steroid Receptors Proteins 0.000 description 9
- 229960003473 androstanolone Drugs 0.000 description 9
- 230000002280 anti-androgenic effect Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- 102000015694 estrogen receptors Human genes 0.000 description 8
- 108010038795 estrogen receptors Proteins 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 102000034527 Retinoid X Receptors Human genes 0.000 description 7
- 108010038912 Retinoid X Receptors Proteins 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 102000003702 retinoic acid receptors Human genes 0.000 description 7
- 108090000064 retinoic acid receptors Proteins 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- KNUFNLWDGZQKKJ-ONEGZZNKSA-N 3,4-dimethoxy cinnamaldehyde Chemical compound COC1=CC=C(\C=C\C=O)C=C1OC KNUFNLWDGZQKKJ-ONEGZZNKSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 6
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 6
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 6
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 6
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 102000027411 intracellular receptors Human genes 0.000 description 6
- 108091008582 intracellular receptors Proteins 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 6
- 102000006255 nuclear receptors Human genes 0.000 description 6
- 108020004017 nuclear receptors Proteins 0.000 description 6
- 102000054765 polymorphisms of proteins Human genes 0.000 description 6
- 102000003998 progesterone receptors Human genes 0.000 description 6
- 108090000468 progesterone receptors Proteins 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical group C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 5
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- YXLFQKUIZVSIEP-UHFFFAOYSA-N Dihydromethyleugenol Chemical compound CCCC1=CC=C(OC)C(OC)=C1 YXLFQKUIZVSIEP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 229940126585 therapeutic drug Drugs 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- FLOPKVGREPTEDA-UHFFFAOYSA-N 2-(4-hydroxy-3-methoxyphenyl)prop-2-enal Chemical group COC1=CC(C(=C)C=O)=CC=C1O FLOPKVGREPTEDA-UHFFFAOYSA-N 0.000 description 4
- FUIVZEHLMVQWHE-UHFFFAOYSA-N 8-(3,4-dimethoxyphenyl)-4-hydroxyocta-3,5,7-trien-2-one Chemical compound COC1=CC=C(C=CC=CC(O)=CC(C)=O)C=C1OC FUIVZEHLMVQWHE-UHFFFAOYSA-N 0.000 description 4
- KNUFNLWDGZQKKJ-UHFFFAOYSA-N Anticancer Benzenoid PMV70P691-57 Natural products COC1=CC=C(C=CC=O)C=C1OC KNUFNLWDGZQKKJ-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- GMEONFUTDYJSNV-UHFFFAOYSA-N Ethyl levulinate Chemical compound CCOC(=O)CCC(C)=O GMEONFUTDYJSNV-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000000051 antiandrogen Substances 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 235000012754 curcumin Nutrition 0.000 description 4
- 239000004148 curcumin Substances 0.000 description 4
- 229940109262 curcumin Drugs 0.000 description 4
- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 description 4
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 3
- HJBWJAPEBGSQPR-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=C(C=CC(O)=O)C=C1OC HJBWJAPEBGSQPR-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 208000017701 Endocrine disease Diseases 0.000 description 3
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZHXZSNNBXPWZFT-JMLMEZNISA-N [H]C1(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)CC(C2=CC(OC)=C(OC)C=C2)(C([H])(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)CC1=O Chemical compound [H]C1(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)CC(C2=CC(OC)=C(OC)C=C2)(C([H])(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)CC1=O ZHXZSNNBXPWZFT-JMLMEZNISA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 102000001307 androgen receptors Human genes 0.000 description 3
- 206010068168 androgenetic alopecia Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000003935 benzaldehydes Chemical class 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960005309 estradiol Drugs 0.000 description 3
- 229930182833 estradiol Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910003480 inorganic solid Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 3
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 3
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- JKHPOPCIKQQRPU-UHFFFAOYSA-N 3-chloro-2-(methoxymethoxy)prop-1-ene Chemical compound COCOC(=C)CCl JKHPOPCIKQQRPU-UHFFFAOYSA-N 0.000 description 2
- MTVIFYGHTHZUKX-UHFFFAOYSA-N 4-acetyl-5-oxohexanoic acid Chemical compound CC(=O)C(C(C)=O)CCC(O)=O MTVIFYGHTHZUKX-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- YMIZGNOSQWXYOH-SZJWQKMJSA-N CCOC(=O)CCC(=O)/C=C/C1=CC=C(O)C(OC)=C1.CCOC(=O)CCC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.CCOC(=O)OC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.COC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.COC1=CC=C(/C=C/C(=O)CCC(C)=O)C=C1OC Chemical compound CCOC(=O)CCC(=O)/C=C/C1=CC=C(O)C(OC)=C1.CCOC(=O)CCC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.CCOC(=O)OC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.COC(=O)/C=C/C1=CC=C(OC)C(OC)=C1.COC1=CC=C(/C=C/C(=O)CCC(C)=O)C=C1OC YMIZGNOSQWXYOH-SZJWQKMJSA-N 0.000 description 2
- XSPGMNPGSJQBPF-MIGZPOJLSA-N COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC Chemical compound COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC XSPGMNPGSJQBPF-MIGZPOJLSA-N 0.000 description 2
- MQHRZKYIPPOYSL-HWWAMZRPSA-N COC1=CC=C(/C=C/C(=O)C(C(=O)/C=C/C2=CC=C(OC)C=C2)=C(O)/C=C/C2=CC=C(OC)C=C2)C=C1.COC1=CC=C(/C=C/C(O)=C(C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC Chemical compound COC1=CC=C(/C=C/C(=O)C(C(=O)/C=C/C2=CC=C(OC)C=C2)=C(O)/C=C/C2=CC=C(OC)C=C2)C=C1.COC1=CC=C(/C=C/C(O)=C(C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC MQHRZKYIPPOYSL-HWWAMZRPSA-N 0.000 description 2
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101000928259 Homo sapiens NADPH:adrenodoxin oxidoreductase, mitochondrial Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000023984 PPAR alpha Human genes 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 229960001445 alitretinoin Drugs 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 201000002996 androgenic alopecia Diseases 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910052810 boron oxide Inorganic materials 0.000 description 2
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000002701 cell growth assay Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- MIPQCGGLMXTKGQ-UHFFFAOYSA-N ethyl 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]hepta-4,6-dienoate Chemical compound C=1C=C(O)C(OC)=CC=1C=CC(=O)C(CCC(=O)OCC)=C(O)C=CC1=CC=C(O)C(OC)=C1 MIPQCGGLMXTKGQ-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 230000003779 hair growth Effects 0.000 description 2
- 102000046818 human AR Human genes 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 201000010066 hyperandrogenism Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940030980 inova Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002395 mineralocorticoid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920000155 polyglutamine Polymers 0.000 description 2
- 108010040003 polyglutamine Proteins 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000000007 protein synthesis inhibitor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 238000001403 relative X-ray reflectometry Methods 0.000 description 2
- 150000004492 retinoid derivatives Chemical group 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 108020003113 steroid hormone receptors Proteins 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 2
- 229940035722 triiodothyronine Drugs 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical compound CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- UWLHSHAHTBJTBA-UHFFFAOYSA-N 1-iodooctane Chemical compound CCCCCCCCI UWLHSHAHTBJTBA-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- IWSVLBKHBJGMAA-UHFFFAOYSA-M 2-(3-benzyl-4-methyl-1,3-thiazol-3-ium-5-yl)ethanol;chloride Chemical compound [Cl-].CC1=C(CCO)SC=[N+]1CC1=CC=CC=C1 IWSVLBKHBJGMAA-UHFFFAOYSA-M 0.000 description 1
- AUZFRUHVDNDVJI-UHFFFAOYSA-N 3-acetylpentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)C(C)=O AUZFRUHVDNDVJI-UHFFFAOYSA-N 0.000 description 1
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- BAKYASSDAXQKKY-UHFFFAOYSA-N 4-Hydroxy-3-methylbenzaldehyde Chemical compound CC1=CC(C=O)=CC=C1O BAKYASSDAXQKKY-UHFFFAOYSA-N 0.000 description 1
- ZIUSSTSXXLLKKK-UHFFFAOYSA-N 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 ZIUSSTSXXLLKKK-UHFFFAOYSA-N 0.000 description 1
- KCQNNJGJUHEQHD-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)hept-6-ene-2,5-dione Chemical compound COC1=CC=C(C=CC(=O)CCC(C)=O)C=C1OC KCQNNJGJUHEQHD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000005676 Adrenogenital syndrome Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- PAJSBEAEKOOOMQ-GRUAZYLMSA-N BrC/C=C/C1=CC=CC=C1.C.C.C.C.C.C.CC(=O)OCBr.COC1=CC=C(/C=C/C(=O)/C(=C\OC(C)=O)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C(\C/C=C/C2=CC=CC=C2)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC Chemical compound BrC/C=C/C1=CC=CC=C1.C.C.C.C.C.C.CC(=O)OCBr.COC1=CC=C(/C=C/C(=O)/C(=C\OC(C)=O)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C(\C/C=C/C2=CC=CC=C2)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC PAJSBEAEKOOOMQ-GRUAZYLMSA-N 0.000 description 1
- ZCFUIBLQGOGVGH-CBDXGXRXSA-N C.C.C.C.C#CC/C(C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC)C=C1.C#CCBr.C=CC/C(C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC)C=C1.C=CCBr.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC Chemical compound C.C.C.C.C#CC/C(C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC)C=C1.C#CCBr.C=CC/C(C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC)C=C1.C=CCBr.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC ZCFUIBLQGOGVGH-CBDXGXRXSA-N 0.000 description 1
- DCYYZZDHGCOZOE-CNXCSKDXSA-N C.C.C.C.C.C.C.CC(=O)Cl.CCOC(=O)CCC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.CCOC(=O)CCC(C)=O.CCOC(=O)Cl.CCOC(=O)OC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.COC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.COC1=C(OC)C=C(/C=C/C(=O)O)C=C1.COC1=C(OC)C=C(/C=C/C(=O)O)C=C1.O=BB(O)O.[H]C(=O)C1=CC(OC)=C(O)C=C1.[H]C(=O)C1=CC(OC)=C(OC)C=C1 Chemical compound C.C.C.C.C.C.C.CC(=O)Cl.CCOC(=O)CCC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.CCOC(=O)CCC(C)=O.CCOC(=O)Cl.CCOC(=O)OC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.COC(=O)/C=C/C1=CC(OC)=C(OC)C=C1.COC1=C(OC)C=C(/C=C/C(=O)O)C=C1.COC1=C(OC)C=C(/C=C/C(=O)O)C=C1.O=BB(O)O.[H]C(=O)C1=CC(OC)=C(O)C=C1.[H]C(=O)C1=CC(OC)=C(OC)C=C1 DCYYZZDHGCOZOE-CNXCSKDXSA-N 0.000 description 1
- OJONKYLPCPWGMO-UTALYJIHSA-N C.C.C.C.C.C.C.CC.CCN(CC)C(=C\C(=O)/C=C/C1=CC(OC)=C(OC)C=C1)/C=C/C1=CC=C(OC)C(OC)=C1.CCNCC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(C)=C/C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.[H][C@@](N)(CO)C1=CC=CC=C1.[H][C@](CO)(NC(=C\C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)/C=C/C1=CC(OC)=C(OC)C=C1)C1=CC=CC=C1 Chemical compound C.C.C.C.C.C.C.CC.CCN(CC)C(=C\C(=O)/C=C/C1=CC(OC)=C(OC)C=C1)/C=C/C1=CC=C(OC)C(OC)=C1.CCNCC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(C)=C/C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.[H][C@@](N)(CO)C1=CC=CC=C1.[H][C@](CO)(NC(=C\C(=O)/C=C/C1=CC=C(OC)C(OC)=C1)/C=C/C1=CC(OC)=C(OC)C=C1)C1=CC=CC=C1 OJONKYLPCPWGMO-UTALYJIHSA-N 0.000 description 1
- UZNYLHHWNVRMRJ-AJHSQPAVSA-N C.C.C.C.C.C.CCN(CC)C(=O)C/C(C(=O)/C=C/C1=CC=C(O)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(O)C=C1.CCN(CC)C(=O)C/C(C(=O)/C=C/C1=CC=C(OC2CCCCO2)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC2CCCCO2)C=C1.CCN(CC)C(=O)CCl.CCOC(=O)C/C(C(=O)/C=C/C1=CC=C(O)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(O)C=C1.CCOC(=O)C/C(C(=O)/C=C/C1=CC=C(OC2CCCCO2)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC2CCCCO2)C=C1.CCOC(=O)CBr.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(O)C=C2)=CC=C1O.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC3CCCCO3)C=C2)=CC=C1OC1CCCCO1.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC3CCCCO3)C=C2)=CC=C1OC1CCCCO1.OC1CCCCO1.[3H][PH](P)=S.[3H][PH](P)=S.[3H][PH](P)=S.[NaH] Chemical compound C.C.C.C.C.C.CCN(CC)C(=O)C/C(C(=O)/C=C/C1=CC=C(O)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(O)C=C1.CCN(CC)C(=O)C/C(C(=O)/C=C/C1=CC=C(OC2CCCCO2)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC2CCCCO2)C=C1.CCN(CC)C(=O)CCl.CCOC(=O)C/C(C(=O)/C=C/C1=CC=C(O)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(O)C=C1.CCOC(=O)C/C(C(=O)/C=C/C1=CC=C(OC2CCCCO2)C(OC)=C1)=C(O)\C=C\C1=CC(CO)=C(OC2CCCCO2)C=C1.CCOC(=O)CBr.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(O)C=C2)=CC=C1O.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC3CCCCO3)C=C2)=CC=C1OC1CCCCO1.COC1=CC(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC3CCCCO3)C=C2)=CC=C1OC1CCCCO1.OC1CCCCO1.[3H][PH](P)=S.[3H][PH](P)=S.[3H][PH](P)=S.[NaH] UZNYLHHWNVRMRJ-AJHSQPAVSA-N 0.000 description 1
- JWWMBXZWBZNCDH-ZQLSMMFWSA-N C.C.C.C.C.C.COC1=CC=C(/C=C/C(O)=C(\CC(N)=O)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.NC(=O)CI.[H]C(=O)/C(C(=O)/C=C/C1=CC(CO)=C(OC)C=C1)=C(O)\C=C\C1=CC=C(OC)C(OC)=C1 Chemical compound C.C.C.C.C.C.COC1=CC=C(/C=C/C(O)=C(\CC(N)=O)C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C(O)=C/C(=O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.NC(=O)CI.[H]C(=O)/C(C(=O)/C=C/C1=CC(CO)=C(OC)C=C1)=C(O)\C=C\C1=CC=C(OC)C(OC)=C1 JWWMBXZWBZNCDH-ZQLSMMFWSA-N 0.000 description 1
- VIFMJXWOQOWOCA-NWRXJLBPSA-N C.C.C.C.CC(=O)CC(C)=O.CCCC1=CC(OC)=C(OC)C=C1.COC1=C(OC)C=C(/C=C/C=C/C(O)=C/C(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=C/C(O)=C/C(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(C=O)C=C1OC Chemical compound C.C.C.C.CC(=O)CC(C)=O.CCCC1=CC(OC)=C(OC)C=C1.COC1=C(OC)C=C(/C=C/C=C/C(O)=C/C(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=C/C(O)=C/C(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(/C=C/C=C/C(=O)/C=C(O)/C=C/C=C/C2=CC(OC)=C(OC)C=C2)C=C1OC.COC1=CC=C(C=O)C=C1OC VIFMJXWOQOWOCA-NWRXJLBPSA-N 0.000 description 1
- NJUMHQIRCFRSRA-LHHGMOFMSA-N C.C.CC(=O)OCBr.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.[H]C1(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)CC(C2=CC(OC)=C(OC)C=C2)(C([H])(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)CC1=O Chemical compound C.C.CC(=O)OCBr.COC1=CC=C(/C=C/C(=O)/C=C(O)/C=C/C2=CC(CO)=C(OC)C=C2)C=C1OC.[H]C1(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)CC(C2=CC(OC)=C(OC)C=C2)(C([H])(C(=O)/C=C/C2=CC=C(OC)C(OC)=C2)C(=O)/C=C/C2=CC(OC)=C(OC)C=C2)CC1=O NJUMHQIRCFRSRA-LHHGMOFMSA-N 0.000 description 1
- IRWRYHFIYLATHS-ZHPLPMSWSA-N C.C.CC1=CC(C=O)=CC=C1O.CCOC(=O)CC/C(C(=O)/C=C/C1=CC=C(O)C(C)=C1)=C(O)\C=C\C1=CC(C)=C(O)C=C1.CCOC(=O)CCC(C(C)=O)C(C)=O Chemical compound C.C.CC1=CC(C=O)=CC=C1O.CCOC(=O)CC/C(C(=O)/C=C/C1=CC=C(O)C(C)=C1)=C(O)\C=C\C1=CC(C)=C(O)C=C1.CCOC(=O)CCC(C(C)=O)C(C)=O IRWRYHFIYLATHS-ZHPLPMSWSA-N 0.000 description 1
- GNDLQTYUXBBKBW-GMGHBIMRSA-N C.C=CC(C)=O.CCCC1=CC(OC)=C(OC)C=C1.CCOC(=O)CCC(=O)/C=C/C1=CC(OC)=C(O)C=C1.CCOC(=O)CCC(C)=O.COC1=C(OC)C=C(/C=C/C(=O)CCC(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.O=BB(O)O Chemical compound C.C=CC(C)=O.CCCC1=CC(OC)=C(OC)C=C1.CCOC(=O)CCC(=O)/C=C/C1=CC(OC)=C(O)C=C1.CCOC(=O)CCC(C)=O.COC1=C(OC)C=C(/C=C/C(=O)CCC(C)=O)C=C1.COC1=C(OC)C=C(/C=C/C=O)C=C1.O=BB(O)O GNDLQTYUXBBKBW-GMGHBIMRSA-N 0.000 description 1
- OPVWCACYZIYNOZ-UHFFFAOYSA-N C=Cc(cc(C=O)cc1)c1O Chemical compound C=Cc(cc(C=O)cc1)c1O OPVWCACYZIYNOZ-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 244000008991 Curcuma longa Species 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 108700020911 DNA-Binding Proteins Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000025309 Hair disease Diseases 0.000 description 1
- 101000836540 Homo sapiens Aldo-keto reductase family 1 member B1 Proteins 0.000 description 1
- 101000809450 Homo sapiens Amphiregulin Proteins 0.000 description 1
- 101000578940 Homo sapiens PDZ domain-containing protein MAGIX Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 102100028326 PDZ domain-containing protein MAGIX Human genes 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 1
- 102100033909 Retinoic acid receptor beta Human genes 0.000 description 1
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 101710151387 Serine protease 1 Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710119665 Trypsin-1 Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- XJMXIWNOKIEIMX-UHFFFAOYSA-N bromo chloro 1h-indol-2-yl phosphate Chemical compound C1=CC=C2NC(OP(=O)(OBr)OCl)=CC2=C1 XJMXIWNOKIEIMX-UHFFFAOYSA-N 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 208000034653 disorder of pilosebaceous unit Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- YCFZXVXRSMJJCU-UHFFFAOYSA-N ethyl 6-(3,4-dimethoxyphenyl)-4-oxohex-5-enoate Chemical compound CCOC(=O)CCC(=O)C=CC1=CC=C(OC)C(OC)=C1 YCFZXVXRSMJJCU-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229940124600 folk medicine Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108091008147 housekeeping proteins Proteins 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 208000018360 neuromuscular disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 108091008761 retinoic acid receptors β Proteins 0.000 description 1
- 108091008760 retinoic acid receptors γ Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- CMHHITPYCHHOGT-UHFFFAOYSA-N tributylborane Chemical compound CCCCB(CCCC)CCCC CMHHITPYCHHOGT-UHFFFAOYSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/73—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with hydrogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
- C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
- C07C49/248—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to compounds with biological activity and pharmaceutical and cosmetic formulations thereof, their derivatives and methods of use, more specifically the present invention includes compounds with at least one (substituted phenyl)-propenal moiety and their biological activity and use thereof.
- curcumin and many of its analogs have been reported to possess numerous biological activities in vitro, such as, anti-oxidant, anti-inflammatory, anti-tumor, and antiangiogenesis activities; but neither curcumin nor its analogues have been developed into a therapeutic drug to treat human diseases. This indicates curcumin in its native form is probably not an optimal molecule for development into a therapeutic drug.
- ASC-J9 and ASC-J15 (5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoic acid ethyl ester) ( FIG. 1 ), both possess potent prostate cancer inhibitory and anti-androgenic activity. These two compounds, in our hand, also exhibited more potent anti-prostate cancer activity than a current therapeutic drug hydroxyl flutamide (HF), a class of “non-steroid anti-androgen” drug that is widely used to treat human prostate cancer.
- HF hydroxyl flutamide
- the present invention provides biologically active compounds having at least one (substituted phenyl)-propenal moiety.
- a medical condition such as a human medical condition.
- a compound having at least one (substituted phenyl)-propenal moiety is provided, the compound having the formula according to formula I:
- R 3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl.
- the compound has formula selected from the group consisting of monomers 1, 3, 5, 6 and 7. These monomers are provided below:
- a compound including a (substituted phenyl)-propenal moiety having the formula according to (IIa) or (IIb):
- R 3 , R 4 , R 3 and R 4 are independently selected from the group consisting of —H, —OH, and —OCH 3 ; 2) L is a C0-C8 alkylene or L is an unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR 1 , —CO 2 R 1 , —CONR 1 R 2 , —NR 1 R 2 , —CX 3 , wherein R 1 and R 2 are independently selected from the group consisting of —H, —CH 3 , and —C 2 H 5 ; and 4) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br.
- the formula IIa and IIb are the equilibrate tautomers as a common phenomenon of diketone.
- the compound is selected from the group consisting of II-1, II-2, II-3, II-4 and II-5.
- R 3 , R 4 , R 3 ′, and R 4 ′ are independently selected from the group consisting of —H, —OH, and —OCH 3 ; and 2) R 1 , and R 2 are independently selected from the group consisting of —H, —CH 3 , —C 2 H 5 , a substituted aryl and a substituted benzyl group.
- R 3 , R 4 , R 3 ′, R 4 ′, R 3 ′′, and R 4 ′′ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
- the compound includes the formula III-1 or III-2, which is provided as:
- R 3 , R 4 , R 3′ , R 4′ , R 3′′ , R 3′′′ , and R 4′′′ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
- the compound includes the formula IV-1:
- each “n” is independently 1, 2, or 3; 2) R 3 , R 4 , R 3 and R 4 are independently selected from the group consisting of —H, —OH, and —OCH 3 ; 3) L-Z side chain can be no-exist, but if L-Z side chain exists, L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR 1 , —CO 2 R 1 , —CONR 1 R 2 , —NR 1 R 2 , —CX 3 ; 5) R 1 and R 2 are independently selected from the group consisting of —H, —CH 3 , and —C 2 H 5 ; and 6) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br.
- a pharmaceutical formulation or cosmetic formulation including a compound including at least one (substituted phenyl)-propenal moiety as provided in the present application and having a desired biological activity.
- the pharmaceutical formulation or cosmetic formulation may provide a compound of the present invention and a pharmaceutically acceptable carrier or a cosmetically acceptable carrier.
- the compound may include monomer 1, 3, 5, 6 or 7 alone or in combination.
- the compound includes the formula according to formulas I, II, III, IV, V, or a combination thereof.
- the compound may include at least one, two, three, four, five or more (substituted phenyl)-propenal moieties.
- a method of treating a medical condition including administering a compound including at least one (substituted phenyl)-propenal moiety having a desired or suspected of having a desired biological activity to an individual in need thereof.
- the compound may be any disclosed herein alone or in combination.
- the compounds of the present invention may be used to treat, prevent or ameliorate symptoms from androgen associated disorders.
- Nonlimiting examples of medical conditions that may be treated with the disclosed compounds are androgen associated inflammation including a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, and alopecia; Kennedy's disease; cancers such as prostate cancer, bladder cancer, liver cancer, and breast cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof.
- FIG. 1 depicts a structural representation of compounds ASC-J9 (1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one) and ASC-J15 (5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoic acid ethyl ester), which were previously shown to have anti-androgenic activities.
- FIG. 2 depicts a table including a nonlimiting listing of newly synthesized compounds encompassed by the present invention including at least one (substituted phenyl)-propenal moiety, with their structures, chemical formulas and molecular weights.
- FIG. 3 depicts a table of Western Blot densitometric data showing compounds having different number of (4-hydroxy-3-methoxy-phenyl)-propenal moieties are capable of reducing Androgen Receptor (AR) expression in human prostate cancer CWR22Rv1 cells.
- AR Androgen Receptor
- FIG. 4 depicts Western Blot images showing newly provided compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing Androgen Receptor (AR) protein expression in human prostate cancer CWR22Rv1 cells.
- AR Androgen Receptor
- FIG. 5 depicts a table showing some selected ASC compounds and monomers are capable of inhibiting proliferation of human prostate cancer cells (LNCaP and CWR22Rv1) stimulated by DHT in vitro.
- FIG. 6 depicts Western Blot data showing four compounds ASC-Q49, ASC-Q103, ASC-JM12, and ASC-JM4, at various concentrations, are capable of reducing endogenous AR expression in LNCaP and CWR22Rv1 human prostate cancer cells.
- FIG. 7 depicts Western Blot data showing compounds ASC-J9 and ASC-JM5 enhances AR protein degradation in the presence of a protein synthesis inhibitor, cycloheximide (CHX), tested in LNCaP cells.
- CHX cycloheximide
- FIG. 8 depicts two tables (8a and 8b) that summarize the potency of representative ASC compounds in reducing endogenous AR protein expression (using Western Blot analysis) at various concentrations, when tested in LNCaP and CWR22Rv1 human prostate cancer cells.
- (substituted phenyl)-propenal moiety refers to a composition including a phenyl group having attached thereto a propenal moiety (when m equals 1) and an alkoxy or hydroxy moiety, or an alkyl or substituted alkyl moiety.
- the substitutions may be positioned meta or para or ortho with respect to the propenal moiety as used herein and refers to a general formula
- alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g. methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
- alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g. ethenyl, prop-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
- alkenylene refers to a straight or branched hydrocarbon chain which contains a carbon-to-carbon double bond and is represented by the formula C n H 2n-2 , wherein hydrogen may be replaced by an additional carbon-to-carbon double bond or a monovalent substituent, e.g. ethenylene, prop-1-enylene and the like.
- alkoxy refers to the radical having the formula —OR wherein R is an alkyl, haloalkyl or cycloalkyl.
- An “optionally substituted alkoxy” refers to the radical having the formula —OR wherein R is an optionally substituted alkyl as described herein.
- alkynl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g. ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.
- aryl refers to a radical of carbocyclic ring system wherein at least one of the rings is aromatic.
- the aryl may be fully aromatic or may contain an aromatic ring in combination with a non-aromatic ring.
- a “biaryl system” is a compound that includes at least two aryl groups.
- cycloalkyl refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- di-ketone bridge refers to a straight or branched hydrocarbon chain including two ketones or an enol positioned in close proximity to a ketone respectively.
- the “di-ketone bridge” or “ketone-enol bridge” is positioned between at least two aryl moieties.
- hydroxyalkyl refers to a straight or branched hydroxy substituted hydrocarbon chain radical having from one to ten carbon atoms, e.g. —CH 2 OH, —(CH 2 ) 2 OH and the like.
- DHT dihydrotestosterone
- DHT is the converted product of testosterone by the 5-alpha-reductase enzyme. Androgen stimulates or controls the development and maintenance of masculine characteristics and other physiological functions in vertebrates by binding to androgen receptors, which in turn binds to the androgen/AR-controlled genes (DNA) and activates or modulates the gene.
- DNA androgen/AR-controlled genes
- AR refers to the intracellular receptor that specifically binds androgens, including testosterone and DHT. AR includes all mammalian isoforms, splice variants and polymorphisms of the androgen receptor.
- estradiol the main endogenous estrogen
- ER the intracellular receptor specific for estradiol (the main endogenous estrogen). When bound to a hormone, it acts as a transcription factor (it regulates the reading of DNA and production of proteins).
- ER includes ER ⁇ and ER ⁇ .
- ER includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
- glucocorticoid receptor refers to the intracellular receptor that has a high affinity to cortisol and other glucocorticoids.
- GR includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
- progesterone receptor refers to the intracellular steroid receptor that specifically binds progesterone. PR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- PPAR peroxisome proliferator activated receptor
- PPAR ⁇ increases transcription of target genes by binding to a specific nucleotide sequence in the gene's promoter.
- RXR retinoid X receptor
- PPAR ⁇ is activated by prostaglandins and leukotrienes and regulates the gene expression of proteins involved in the storage of fatty acids.
- PAR ⁇ is weakly activated by fatty acids, prostaglandins, and leukotrienes. Its physiological ligand has not been identified.
- retinoic acid receptor or “RAR” as used herein refers to the intracellular receptor known to bind many retinoid forms. “RAR” includes all family members, which include RAR ⁇ , RAR ⁇ and RAR ⁇ . “RAR” includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- RXR retinoid x receptor
- RXR retinoid x receptor
- RXR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- steroid receptor or “steroid nuclear receptor” as used herein refers to intracellular receptors that bind to and regulate the transcription of DNA under the regulation of steroid hormones. Receptors for the different hormones have strong structural and functional similarities which point to an evolution from a common ancestral gene and therefore are considered a gene superfamily.
- Representative receptors which belong to this gene superfamily include the DNA binding and regulatory proteins controlled by the steroid hormones estradiol (ER), glucocorticoid (GR), androgen (AR), progesterone (PR), mineralocorticoid (MR), the nonsteroid hormones triiodothyronine (T3R) and dihydroxyvitamin D3 (VDR), and two classes of retinoid (all-trans retinoic acid and 9-cis retinoic acid) receptors (RARs and RXRs respectively). More than 32 genes encoding at least 75 proteins with different DNA specificity, regulation, or hormone affinity have been identified as part of this gene superfamily.
- Steps of this superfamily are being reported frequently and are herein intended to be incorporated by reference in their entirety as published in peer reviewed scientific literature or as provided in sequence databases such as GenBank, whether DNA, RNA or polypeptide sequence, and SWISSPROT. Using new biotechnology, molecular biologists and biochemists have identified protein receptors for which the ligands have not yet been identified, thus giving birth to a class of “orphan receptors”. “Steroid receptor” includes all mammalian splice variants and isoforms of the steroid receptors.
- extended release refers to dosage form that provides for the delayed, slowed over a period of time, continuous, discontinuous, or sustained release of a compound or composition.
- pharmaceutically acceptable refers to approved or approvable by a regulatory agency of the Federal or a state government for use in animals, and more particularly in humans.
- pharmaceutically acceptable carrier refers to an approved or approvable diluent, adjuvant, excipient or carrier with which a compound is administered.
- prodrug refers to a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
- the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
- the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
- the prodrug includes a cleavable ester, which upon cleavage, releases the active form.
- terapéuticaally effective amount refers to the amount of a compound that, when administered to a patient for treating a disease or disorder, is sufficient to affect such treatment for the disease or disorder.
- the “therapeutically effective amount” will vary depending on the compound, the disease or disorder and its severity and the age and weight of the patient to be treated.
- the “therapeutically effective amount” may include a series of administrations that eventually causes a desired effect whether or not the initial administration is effective.
- derivative refers to variations on a core structure or pharmacophore that yields a desired effect. Derivatives may include substitutions along the phenyl ring, the propenal region of the molecule or along a side chain. Thus derivatives encompassed herein include compounds formed from or include at least one disclosed compound, such as those identified in formulas I, II, III, IV, or V. It may be desirable to form derivatives of the particular compounds to modulate solubility, efficacy, aggregation and the like.
- the inventors of the present invention have found that compounds described herein, including those with at least one (substituted phenyl)-propenal moiety show promise for the treatment or prevention of medical conditions. Moreover compounds disclosed herein are believed to possess activities, such as reducing the proliferation of cells that are believed to have or suspected of having a cancerous profile. Additionally, compounds disclosed herein demonstrate the ability to selectively modulate populations of steroid receptors. Thus it is an object of the present invention to provide compounds having biological activities useful in the treatment or prevention of disease in mammals, such as humans.
- compositions disclosed herein may be provided or administered as compounds themselves or may be adapted with a suitable carrier to effect the desired treatment.
- the compounds When providing the compounds disclosed herein as a pharmaceutical, the compounds may be provided in combination with a pharmaceutically acceptable carrier.
- the compounds disclosed herein as a cosmetic When providing the compounds disclosed herein as a cosmetic, the compounds may be provided in combination with a cosmetically acceptable carrier.
- Pharmaceutically acceptable carriers and cosmetically acceptable carriers may be the same, may be derived from one another and the like as known in the pharmaceutical and cosmetic industries, or may be different such as but not limited to variations depending on desired route of administration.
- Compounds may be tested for solubility, activity and dipole moment before or after the preparation as a pharmaceutical or cosmetic and may be tested alone or in combination with other compounds disclosed herein for synergistic effects.
- the present invention includes one or more compound and derivatives thereof, including those with hydrophilic or hydrophobic additions, substitutions or subtractions.
- a compound having at least one (substituted phenyl)-propenal moiety is provided.
- compounds having a (substituted phenyl)-propenal moiety have biological activity including anti-androgen/anti-AR biological activity.
- the (substituted phenyl)-propenal moiety has the formula according to formula I:
- R 3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl.
- X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl.
- compounds having at least one (substituted phenyl)-propenal moiety are capable of decreasing the presence of the androgen receptor or inducing degradation of the androgen receptor.
- compounds having at least one (substituted phenyl)-propenal moiety were shown to reduce cancer cell growth or proliferation of cancer cells. Such inhibition occurred in the presence of a compound capable of cancer cell stimulation.
- the compound includes a (substituted phenyl)-propenal compound or a pharmaceutically acceptable salt thereof, selected from monomer
- derivatives of the above referenced monomers having biological activity are also provided.
- the derivatives may have substitutions at one or more positions to increase one or more characteristic such as activity, solubility and the like.
- Such derivatives may modulate the dipole moment of a compound and may result in a composition that is more or less hydrophobic or hydrophilic.
- a compound including a (substituted phenyl)-propenal moiety having the formula according to (Ia) or (IIb):
- R 3 , R 4 , R 3 , and R 4 are independently selected from the group consisting of —H, —OH, and —OCH 3 ; 2) L is a C0-C8 alkylene or L is an unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR 1 , —CO 2 R 1 , —CONR 1 R 2 , —NR 1 R 2 , —CX 3 , wherein R 1 and R 2 are independently selected from the group consisting of —H, —CH 3 , and —C 2 H 5 ; 4) X is halogen atom selected from the group consisting of —F, —Cl, and —Br; and further wherein the formula IIa and IIb are the equilibrate tautomers as a common phenomenon of diketone.
- the compound IIa and IIb
- R 3 , R 4 , R 3 and R 4 ′ are independently selected from the group consisting of —H, —OH, and —OCH 3 ; and 2) R 1 , and R 2 are independently selected from the group consisting of —H, —CH 3 , —C 2 H 5 , a substituted aryl and a substituted benzyl group.
- R 3 , R 4 , R 3 ′, R 4 ′, R 3 ′′ and R 4 ′′ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
- Nonlimiting examples include those with the formula III-1 or III-2:
- R 3 , R 4 , R 3′ , R 4′ , R 3′′ , R 4′′ , R 3′′′ , and R 4′′′ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
- the compound has the formula IV-1:
- each “n” is independently 1, 2, or 3; 2) R 3 , R 4 , R 3 ′, and R 4 ′ are independently selected from the group consisting of —H, —OH, and —OCH 3 ; 3) L-Z side chain can be no-exist, bur if L-Z side chain exists, L is a C0-C 8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR 1 , —CO 2 R 1 , —CONR 1 R 2 , —NR 1 R 2 , —CX 3 ; 5) R 1 and R 2 are independently selected from the group consisting of —H, —CH 3 , and —C 2 H 5 ; and 6) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br.
- Synthesis of the disclosed compounds may be performed using standard practices known in the organic synthesis arts using known solvents. Synthesized compounds may be tested for desired activity such as degradation of a steroid receptor, such as the androgen receptor, the ability to prevent or inhibit proliferation of cancer cell lines, the reduction of tumor size in grafted animal studies and the like. Compounds identified as hits or leads may be further adapted using the synthesis methods and techniques disclosed herein. Thus, variations on the provided synthetic methods will be readily apparent to those skilled in the art and are deemed to be within the scope of the present invention.
- Example 1 demonstrates a variety of synthesis schemes for the provided monomers as well as derivatives thereof, which are also encompassed herein.
- derivatives are provided as a combination of monomers or portions thereof to form a biphenyl, triphenyl, or quadrophenyl ring system or more.
- a biphenyl ring system was utilized for testing and comparison to other proposed treatments; however compounds having a single (substituted phenyl)-propenal moiety, were also found to have activity such as the ability to prevent proliferation of cancer cell lines stimulated with DHT and the ability to degrade the androgen receptor.
- Some of the compounds of the present invention were prepared through a condensation of substituted benzaldehydes and 2,4-pentanedione or 3-substituted 2,4-pentanedions by the method known in the literature. Pedersen et al., Liebigs Ann. Chem., 1557-1569 (1985).
- the desired substituents on the biphenyl ring and on the C4 of the conjugation bridge were synthesized either before or after the condensation.
- the length of conjugating bridge between the two phenyl moieties could be varied from 5 carbons to 11 carbons through synthetic strategies. Properly adding and removing protecting groups allow ultimate synthesis of disclosed compounds.
- the present invention includes the disclosed compounds themselves, as well as their salts and their prodrugs, if applicable.
- the salts or prodrugs should retain a portion of the desired biological activity of the parent compound or be provided in a form that the body or subject can convert to a biologically active form.
- the salts for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, tartrate, trifluoroacetate, and acetate.
- a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation.
- Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
- Nonlimiting examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the compounds derivatives described above.
- the compounds of the present invention may be formulated for administration for the prevention or treatment of a variety of medical conditions.
- Pharmaceutical formulations may include at least one of the disclosed compounds or pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
- Techniques of pharmaceutical production are well known in the art of the present invention and typically include mixing a compound or salt in the presence of a suitable carrier.
- Suitable carriers for use with the compounds of the present invention include diluents, excipients, or carrier materials, selected according to the intended form of administration and consistent with conventional pharmaceutical or cosmetic practice.
- suitable carriers include, but are not limited to, water, physiological saline, phosphate-buffered saline, a physiologically compatible buffer, saline buffered with a physiologically compatible salt, a water-in-oil emulsion, and an oil-in-water emulsion, an alcohol, dimethylsulfoxide, dextrose, mannitol, lactose, glycerin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like, and mixtures thereof.
- Suitable carriers can also include appropriate pharmaceutically acceptable antioxidants or reducing agents, preservatives, suspending agents, solubilizers, stabilizers, chelating agents, complexing agents, viscomodulators, disintegrating agents, binders, flavoring agents, coloring agents, odorants, opacifiers, wetting agents, pH buffering agents, and mixtures thereof, as is consistent with conventional pharmaceutical practice (“Remington: The Science and Practice of Pharmacy”, 20th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000).
- Suitable routes of administration may include oral, intestinal, parenteral, transmucosal, transdermal, intramuscular, subcutaneous, rectal, intramedullary, intrathecal, intravenous, intraventricular, intraatrial, intraaortal, intraarterial, or intraperitoneal administration.
- compositions of the present invention can be administered to the subject by a medical device, such as, but not limited to, implantable devices, biodegradable implants, patches, and pumps.
- a medical device such as, but not limited to, implantable devices, biodegradable implants, patches, and pumps.
- the compositions may be formulated to include a dissolvable or nondissolvable matrix or medium (for example, a coating, membrane, film, impregnated matrix, polymer, sponge, gel, or porous layer on or within the medical device) to permit the release of the active compound or compounds over a specified period of time.
- compositions of the present invention can be formulated and provided in any formulation suitable to the intended form of administration and consistent with conventional pharmaceutical practice (“Remington: The Science and Practice of Pharmacy”, 20 th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000).
- suitable formulations include tablets, capsules, syrups, elixirs, ointments, creams, lotions, sprays, aerosols, inhalants, solids, powders, particulates, gels, suppositories, concentrates, emulsions, liposomes, microspheres, dissolvable matrices, sterile solutions, suspensions, or injectables, and the like.
- injectables can be prepared in conventional forms either as liquid solutions or suspensions, as concentrates or solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- the present invention includes methods of treating, ameliorating symptoms from or preventing the progression of a variety of medical conditions using the disclosed compounds and compositions, including pharmaceutical and cosmetic formulations.
- the medical conditions may, at least in part, be modulated by a steroid receptor.
- Steroid receptors of particular interest may include but are not limited to androgen receptor (AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptors (RARs and RXRs), and orphan steroid hormone receptors.
- Compositions or compounds of the present invention may target a specific receptor, such as the androgen receptor or may target particular receptors within the steroid receptor superfamily.
- the methods of the present invention may prevent, treat or ameliorate symptoms from cancers such as but not limited to prostate cancer, liver cancer, bladder cancer, cervical cancer, lung cancer and breast cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, endometrial cancer, ovarian cancer, central nervous system cancer, and the like.
- cell lines having a profile of a cancerous cell such as cell lines prepared from cancer cells, may be utilized.
- activities of compounds of the present invention are evaluated for the ability to inhibit cancer cell growth or proliferation, optionally stimulated with a stimulator, such as DHT.
- a stimulator such as DHT.
- Compounds disclosed herein were specifically shown to reduce growth or proliferation of prostate cancer cells.
- the compounds their derivatives, pharmaceutical compositions and the like are used to prevent, treat or ameliorate symptoms from neurological and neuromuscular disorders such as Kennedy Disease.
- Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease is a gender-specific motor neuron disease that affects 1 in every 40,000 males (reviewed by Katsuno et al., 2004).
- SBMA patients have a mutated androgen receptor containing an expanded polyglutamine tract. The expanded polyglutamine androgen receptor forms aggregates that interfere with cell functioning and is the factor that causes the proximal muscle atrophy associated with SBMA.
- the methods of the present invention may include relieving the stress caused by aggregate formation by reducing the amount of the mutant AR to a level that could be more easily policed by the cells' native housekeeping machinery.
- the methods of the present invention may including selectively degrading the androgen receptor and thus may be used as a therapy for SBMA.
- the disclosed compounds that can enhance androgen receptor degradation may suppress the steady-state level of the receptor thus, attenuating the severity of aggregate formation in patients.
- Compounds and compositions of present invention may prevent, treat or ameliorate symptoms from androgen related hair disorders.
- androgenetic alopecia or “male pattern baldness” is hair loss caused by androgen activity on the androgen receptors in follicles and adjacent cells.
- hirsutism is excessive growth of thick dark hair in locations where hair growth in women usually is minimal or absent.
- Such male-pattern growth of terminal body hair usually occurs in androgen-stimulated locations, such as the face, chest, and areolae.
- Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention.
- Compounds and compositions of the present invention may treat inflammation (e.g., rheumatoid arthritis), acne, alopecia, and may accelerate wound healing.
- Acne is caused by androgen-induced AR activation of sebaceous glands and may therefore be treated by administering a compound capable of preventing or decreasing AR activation.
- Compounds of the present invention are believed to induce degradation of the androgen receptor and thus would provide an effective treatment against such medical conditions.
- Androgenetic alopecia and other hair growth disorders are known to cause by the activation of androgen receptors (AR) in hair follicles by endogenous androgen.
- Certain inflammation conditions and wound healing are also believed to be associated with the androgen receptor in response to androgen.
- Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention. Topical application of such formulations may be of particular interest.
- PCOS polycystic ovary syndrome
- Cushing's syndrome congenital adrenal hyperplasia
- non-classical adrenal hyperplasia ovary or adrenal tumor
- iatrogenic androgen excess a malignant ovary syndrome
- hyperandrogenic symptoms can also be detected in human immunodeficiency virus (HIV)-infected women showing lipodystrophy syndrome (Hadigan et al., 2000). It has been suggested that hyperandrogenism may be involved in lipid aberrations observed in the latter group of patients.
- HIV human immunodeficiency virus
- the methods of the present invention include the treatment of a variety of medical conditions as disclosed herein or are believed to be associated at least in part with a steroid or steroid associated disorder.
- the methods of treatment include administering a compound, pharmaceutical formulation or cosmetic formulation of the present invention to an individual or subject in need thereof.
- Subjects may be treated with a therapeutically effective dosage.
- a therapeutically effective dosage may vary somewhat from compound to compound, patient to patient, and will depend on the condition of the patient and route of delivery. As general guidance, a dosage from about 0.1 to about 50 mg/kg may have therapeutic efficacy, while still higher dosages potentially being employed.
- propenal core structural unit (monomers) were prepared through standard and advanced organic syntheses.
- compounds consisting of two or more (substituted phenyl) propenal core structural moieties were prepared by a condensation of substituted benzaldehydes and 2,4-pentanedion or 3-substituted 2,4-pentanedions by the method known in the literature.
- Pedersen et al (Liebigs Ann. Chem., 1557-1569, 1985).
- the desired substituents on the biphenyl ring and on the C4 of conjugation bridge were synthesized either before or after the condensation.
- the length of conjugation bridge between the two phenyl moieties could be varied from 5 carbons to 11 carbons through synthetic strategies. Properly adding and removing protecting groups allow ultimate synthesis of the disclosed derivatives. In addition, various synthetic steps may be performed in an alternate sequence in order to give the desired compounds.
- Derivative phosphate prodrugs were further prepared by reacting compounds having compounds a (substituted phenyl)-propenal moiety with phosphorous oxychloride in an appropriate solvent, e.g., dichloromethane, in the presence of an organic base, e.g., triethylamine.
- Tartrate of disclosed compounds as water-soluble salts were synthesized by reacting compounds having a (substituted phenyl)-propenal moiety with tartaric acid in water.
- Flash column chromatography was performed on silica gel (100-200 mesh) or alumina (aluminum oxide, basic, Brockmann I, standard grade, ⁇ 150 mesh).
- HPLC was conducted on Shimadzu SCL 10A instrument.
- HPFC was conducted on a Biotage system or ISCO Inc.
- Chemflash chromatographic system Preparative thin layer chromatography (PTLC) on silica gel plates (Kieselgel 60, F254, 1.00 mm) were also used for separation and purification.
- Precoated silica gel plates were used for thin layer chromatography (TLC) analysis.
- ASC-J9 was synthesized as starting material by reaction of 3,4-dimethoxybenzaldehyde with 2,4-pentanedione based on a published method (Pedersen et al., Liebigs Ann. Chem., 1557-1569, 1985).
- the monomers structurally with a (3,4-dimethoxy or 3-methoxy, 4-hydroxy substituted phenyl)-propenal moiety, a basic structure of the currently provided compounds, have been synthesized by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid with corresponding reagents (monomers 1, 3), or reaction of 3,4-dimethoxy-benzaldehyde or 3-methoxy-4-hydroxy benzaldehyde with ethyl levulinate (monomers 5 and 6).
- Monomor-7 was synthesized starting from 3-(3,4-dimethoxyphenyl)propane through two steps. More specifically, the synthesis methods for the monomers are described as below and illustrated in Scheme 1.
- Monomer 1,3-(3′,4′-Dimethoxy-phenyl)-acrylic acid methyl ester was synthesized by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid with methanol in the presence of acetic chloride. After refluxing for 2.5 h, the reaction mixture was concentrated by evaporation to 1 ⁇ 3 and the white solid was filtered and dried in vacuo to get the desired product in 76% yield as a white crystalline solid. mp. 74-75° C.
- Monomer 3 a mixed anhydride, was prepared by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid in toluene/CH 2 Cl 2 (1:1) in the presence of Et 3 N. The solution was cooled to 0° C., ethyl chloroformate (1.5 eq.) was added dropwise. After stirring at 0° C. for 2 h, the precipitate was filtered out. The filtrate was concentrated to get a relatively pure white solid, which was purified by a fast filtration through a thin silica gel pad and eluted with hexanes:ethyl acetate (1:0 to 4:1) to afford the desired product as a white solid in quantity.
- Monomer 5 i.e., 6-(3′,4′-Dimethoxy-phenyl)-4-oxo-hex-5-enoic acid ethyl ester
- ethyl levulinate 1 eq.
- boron oxide 0.7 eq
- tributyl borate and 3,4-dimethoxy-1-benzaldehyde both 1 eq.
- Monomer 6,6-(4-Hydroxy-3-methoxy-phenyl)-4-oxo-hex-5-enoic acid ethyl ester was synthesized by reaction of vanillin with ethyl levulinate with a similar method recorded in the synthesis of Monomer 5.
- the desired compound was obtained as a yellow crystalline solid. mp. 55-56° C.
- Monomer 7, i.e., 7-(3,4-Dimethoxy-phenyl)-hept-6-ene-2,5-dione was made by 3-(3,4-dimethoxyphenyl)propane through 2 steps.
- 3,4-dimethoxycinnamaldehyde was made as described in the synthesis of Q110 (Scheme 13) in 60% yield. Dissolving the resulting compound (1 eq.) in dry EtOH, 3-butene-2-one (1 eq.) was added. The reaction solution was heated to 80° C.
- Compounds Q100, Q101, JM1, JM6, and JM7 were made with an unsaturated side chain at C4 position of ASC-J9 intending to enhance anti-prostate cancer activity.
- Compound Q100 was synthesized by reaction of ASC-J9 with 3-bromo-propyne in CH 2 Cl 2 at 60° C. over night in the presence of K 2 CO 3 .
- Compound Q101 was made by reaction of ASC-J9 with bromopropene in DMF at 100° C. for 2 h in the presence of K 2 CO 3 and KI (Scheme 8). The crude compounds were purified by silica gel flash column chromatography eluted by hexanes and EtOAc mixture to get the desired products.
- Compounds Q102-Q104, Q108, JM12-JM14, JM17 were synthesized to evaluate the properties of the C4-alkyl substitution on ASC-J9 with differences in chain length, in ring size, and in functional groups at chain-end (e.g., Q108 and JM14).
- Compounds Q114-Q115, JM16, JM18-19 were synthesized to evaluate the functions of not only the C4-side chain but also the substitutions on the bi-phenyl moiety. All compounds were prepared by reaction of 2,4-pentadione with appropriate alkyl or alkylene (or substituted alkyl or alkylene) bromide or iodine in benzene with DBU as a base.
- reaction mixture was washed with brine and extracted the CH 2 Cl 2 , dried over Na 2 SO 4 and purified by silica gel flash column chromatography to give a mixture of C3-octanyl substituted 2,4-pentadione and O-octyl substituted 2,4-pentadione. Reaction of the mixture with 3,4-methoxybenzaldehyde through the method mentioned above afforded the compound Q104.
- Compounds JM4, JM20, Q116 structurally share the property of a (substituted)-triaryl system [three (substituted phenyl) propenal conjugation].
- One of the purposes to synthesize these compounds is to study the effect of multi-phenyl propenal moiety on anti-AR and anti-prostate cancer activities.
- Compound JM4 were synthesized from a condensation of 3,4-dimethyoxybenzaldehyde with triacetylmethane as shown in Scheme 11.
- compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13.
- Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solution of 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated.
- the crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid.
- a solution of the intermediate (1 eq.) and B 2 O 3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h.
- 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h.
- Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C.
- ASC compounds and monomers were tested for their activity to block androgen/AR-induced functions.
- a cell growth assay using human prostate cancer cells, either LNCaP or CWR22Rv1 was applied in the studies. Functional AR proteins are expressed in both cancer cell lines; whereas the growth of LNCaP cells is DHT dependant, but the growth of CWR22Rv1 cells, derived from a relapsed hormone-refractory tumor, was not.
- Western Blot analysis were performed by testing monomers, and some representative new compounds in prostate cancer cells to demonstrate that compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing AR protein expression levels and inhibiting cancer cell growth in vitro.
- the MTT cell proliferation assay was applied in the present invention to detect the capability of compounds to suppress or inhibit prostate cancer cells growth.
- the MTT assay which is a method widely used to detect proliferation of culture cells and is relied upon the conversion of a colorless substrate to reduced tetrazolium by a mitochondrial dehydrogenase (possessed by all viable cells), and has been demonstrated previously (Su et al., 1999) to assess the growth of various tissue-cultured cells. Briefly, 1 ⁇ 10 3 LNCaP or CWR22Rv1 cells suspended in complete medium were plated into each well of a 96-well Microtest III tissue culture plate (Falcon, N.J.).
- the medium was replaced with RPMI-1640 medium containing 10% charcoal/dextran-deprived FBS (hormone-deprived fetal bovine serum). Testing compounds were added to the medium at indicated concentrations with or without 1 nM DHT and cells were cultured for 5 days in an incubator (at 37° C.). MTT substrate solution (5 mg/ml in PBS) in 1/10 of volume was added to the cells in each well at 2 hours before harvesting. After 2 hour incubation, the plates were centrifuged (10 min at 1,000 rpm) and the supernatant from each well was carefully removed.
- MTT substrate solution 5 mg/ml in PBS
- a 100 ⁇ l of lysis buffer (50% dimethyl formamide, 5% sodium dodecyl sulphate, 0.35 M acetic acid, and 50 mM HCl) was added to each well to lyse the cells and dissolved tetrazolium in each well.
- the relative quantity of enzyme activity from each well was measured based on absorbance read at a wavelength of 450 nm using a Bio-RAD BenchMark microplate reader. Data derived from the MTT assay were also verified by the actual cell count and cell morphology on a separate plate set up in parallel. Data from this parallel plate demonstrated a positive relationship between the quantity of enzyme activity and the number of viable cells in the well.
- a widely used Western Blotting analysis was employed to measure AR protein expression level.
- Human prostate cancer cells, LNCaP and CWR22Rv1 both express high levels of AR proteins and were used in this study.
- representative ASC compounds were tested in Western blot assay to evaluate their activity in reducing AR expression; and the assays were carried out in either the presence or absence of dihydrotestosterone (DHT, 1 nM). After cells were incubated with testing compounds for the designated time, they were harvested and lysed according to Western Blot techniques known in the biochemical arts. Details of Western Blotting analysis method have been published previously (Su et al., 1999).
- cells were harvested either in 2 ⁇ sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS/PAGE) loading buffer or in Radio-Immunoprecipitation Assay (RIPA) lysis buffer strengthened with 10 ⁇ g/ml of benzamidine, 10 ⁇ g/ml of trypsin inhibitor, and 1 mM of phenylmethylsulfonyl fluoride.
- SDS/PAGE sodium dodecyl sulphate/polyacrylamide gel electrophoresis
- RIPA Radio-Immunoprecipitation Assay
- the membrane was then incubated with 10% non-fat milk in phosphate-buffered saline supplemented with 0.1% Tween-20 (PBST) for 1 hour and then followed with an overnight incubation with a primary human AR-specific antibody (purchased from BD-PharMingen) at 4° C. After incubation, the membrane was rinsed with PBST buffer three times; 10 min each time; an alkaline phosphatase-conjugated secondary antibody was then added and incubated for 1 hour at room temperature.
- PBST phosphate-buffered saline supplemented with 0.1% Tween-20
- AR protein “degradation” in prostate cancer cells was measured by using cycloheximide (a protein synthesis inhibitor) chasing assay method. Briefly, LNCaP cells were incubated with testing ASC compound at the designated concentrations for 24 hours. Subsequently, cycloheximide was added to the cells at a concentration of 15 ⁇ g/ml to block new protein synthesis. After incubation, cells were harvested at designated time periods and the resultant change in AR protein levels were analysed using Western Blot analysis as described above.
- cycloheximide a protein synthesis inhibitor
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Reproductive Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
- The present application claims benefit of priority to United Sates patent application Ser. No. 60/879,458 filed on Jan. 8, 2007, which is herein incorporated by reference in its entirety.
- The present invention relates to compounds with biological activity and pharmaceutical and cosmetic formulations thereof, their derivatives and methods of use, more specifically the present invention includes compounds with at least one (substituted phenyl)-propenal moiety and their biological activity and use thereof.
- It is well known that certain natural products may possess therapeutic effects, which has lead to their use in the treatment and prevention of human diseases across many cultures (e.g., Chinese herbal medicines and many other folk medicines). The effectiveness of such treatments has lead the pharmaceutical industry to seek and isolate active compounds from these natural products and develop the active ingredients as therapeutic or prophylactic drugs for the treatment and prevention of a variety of diseases or medical conditions. Thus many commonly used pharmaceuticals have been developed or have arisen from natural products. Among these include, aspirin (acetylsalicylic acid), which was isolated from bark of the willow tree; ephedrine and pseudoephedrine, which were isolated from a Chinese herb Ma Huang; and penicillin, which was isolated from fungus (Pennicillium chrysogenum). However, compounds isolated from natural products are known to play certain physiological function(s) in its native host; whereas their therapeutic effects against human diseases are not readily apparent. Historically, such therapeutic treatments were derived merely by accumulated experiences or “trial and error” in humans. Moreover, because such compounds were not initially created for use in humans, the compounds in their native form are frequently not in the most optimal form, both in structure as well as efficacy, to treat human diseases. However, today's modern chemistry technology, including analytical and synthetic chemistries, together with the advances in medicinal biology have made it possible for one to dissect a chemical structure and localize a “pharmacophore” (a core structure that is essential for the therapeutic activity) within a compound such as one isolated from a natural product; furthermore, these new techniques allow one to synthesize new compounds, based on the structure of a pharmacophore, that possess optimal or even better therapeutic efficacy.
- In this invention we have demonstrated that a compound with a single (4-hydroxy-3-methoxy-phenyl)-propenal moiety possesses an activity that could reduce the expression of androgen receptor (AR) protein by enhancing its degradation. This discovery resulted in part from our extensive study of compound ASC-J9 (1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one), a dimethylated form of a natural compound curcumin (existing as a major pigment in a turmeric plant). Compound curcumin and many of its analogs have been reported to possess numerous biological activities in vitro, such as, anti-oxidant, anti-inflammatory, anti-tumor, and antiangiogenesis activities; but neither curcumin nor its analogues have been developed into a therapeutic drug to treat human diseases. This indicates curcumin in its native form is probably not an optimal molecule for development into a therapeutic drug.
- Previously we have discovered compounds ASC-J9 and ASC-J15 (5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoic acid ethyl ester) (
FIG. 1 ), both possess potent prostate cancer inhibitory and anti-androgenic activity. These two compounds, in our hand, also exhibited more potent anti-prostate cancer activity than a current therapeutic drug hydroxyl flutamide (HF), a class of “non-steroid anti-androgen” drug that is widely used to treat human prostate cancer. - After extensive further study of the structure and bioactivity of ASC-J9 and ASC-J15, we were surprised to find that the (substituted phenyl)-propenal moieties shared by these two compounds are actually the core structure(s) that attribute to the potent anti-androgen/AR activity of these compounds but not the entire curcumin-like structure. Based in part on this finding we have generated, by chemically synthesis, numerous new compounds, including compounds that possess one, two, three or four (substituted phenyl)-propenal moieties to further support the concept that a (substituted phenyl)-propenal moiety is the pharmacophore of these compounds. Results from our study are able to show that the increase in number of these moieties within a compound structure may alter or may increase the anti-androgen/AR activity of the compound. We also demonstrate herein that anti-androgenic activity is present within compounds having a single (substituted phenyl)-propenal moiety. New derivatives, based on our new compounds with at least one (substituted phenyl)-propenal moiety, were also synthesized by the present inventors to elucidate not only the pharmacophore structure but also to evaluate the anti-androgenic and anti-cancer activities. The new compounds, provided herein by the inventors further show significant improvements and optimization of bioactivity, bioavailability, water solubility and other criteria essential for the development of therapeutic drug.
- The present invention provides biologically active compounds having at least one (substituted phenyl)-propenal moiety. Thus it is an object of the present invention to provide compounds having at least one (substituted phenyl)-propenal moiety for use as a treatment for a medical condition, such as a human medical condition.
- In one aspect of the present invention a compound having at least one (substituted phenyl)-propenal moiety is provided, the compound having the formula according to formula I:
- wherein 1) R3 and R4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl. In some embodiments the compound has formula selected from the group consisting of
monomers - Monomers:
- In another aspect of the present invention a compound is provided including a (substituted phenyl)-propenal moiety having the formula according to (IIa) or (IIb):
- wherein: 1) R3, R4, R3 and R4 are independently selected from the group consisting of —H, —OH, and —OCH3; 2) L is a C0-C8 alkylene or L is an unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR1, —CO2R1, —CONR1R2, —NR1R2, —CX3, wherein R1 and R2 are independently selected from the group consisting of —H, —CH3, and —C2H5; and 4) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br. The formula IIa and IIb are the equilibrate tautomers as a common phenomenon of diketone. In some embodiments the compound is selected from the group consisting of II-1, II-2, II-3, II-4 and II-5. The formulas provided as:
- In another aspect of the present invention, a compound is provided according to formula IIc:
- wherein 1) R3, R4, R3′, and R4′ are independently selected from the group consisting of —H, —OH, and —OCH3; and 2) R1, and R2 are independently selected from the group consisting of —H, —CH3, —C2H5, a substituted aryl and a substituted benzyl group.
- In another aspect of the present invention, a compound is provided according to formula III:
- wherein R3, R4, R3′, R4′, R3″, and R4″ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen. In some embodiments, the compound includes the formula III-1 or III-2, which is provided as:
- In another aspect of the present invention, a compound is provided according to the formula IV:
- wherein R3, R4, R3′, R4′, R3″, R3′″, and R4′″ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen. In some embodiments the compound includes the formula IV-1:
- In another aspect of the present invention a compound is provided according to formula V:
- wherein 1) each “n” is independently 1, 2, or 3; 2) R3, R4, R3 and R4 are independently selected from the group consisting of —H, —OH, and —OCH3; 3) L-Z side chain can be no-exist, but if L-Z side chain exists, L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR1, —CO2R1, —CONR1R2, —NR1R2, —CX3; 5) R1 and R2 are independently selected from the group consisting of —H, —CH3, and —C2H5; and 6) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br. In some embodiments the compound is provided according to formula V-1 or V-2:
- In another aspect of the present invention a pharmaceutical formulation or cosmetic formulation is disclosed including a compound including at least one (substituted phenyl)-propenal moiety as provided in the present application and having a desired biological activity. The pharmaceutical formulation or cosmetic formulation may provide a compound of the present invention and a pharmaceutically acceptable carrier or a cosmetically acceptable carrier. In various nonlimiting embodiments, the compound may include
monomer - In another aspect of the present invention a method of treating a medical condition is disclosed including administering a compound including at least one (substituted phenyl)-propenal moiety having a desired or suspected of having a desired biological activity to an individual in need thereof. The compound may be any disclosed herein alone or in combination. The compounds of the present invention may be used to treat, prevent or ameliorate symptoms from androgen associated disorders. Nonlimiting examples of medical conditions that may be treated with the disclosed compounds are androgen associated inflammation including a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, and alopecia; Kennedy's disease; cancers such as prostate cancer, bladder cancer, liver cancer, and breast cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof.
-
FIG. 1 depicts a structural representation of compounds ASC-J9 (1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one) and ASC-J15 (5-Hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6-dienoic acid ethyl ester), which were previously shown to have anti-androgenic activities. -
FIG. 2 depicts a table including a nonlimiting listing of newly synthesized compounds encompassed by the present invention including at least one (substituted phenyl)-propenal moiety, with their structures, chemical formulas and molecular weights. -
FIG. 3 depicts a table of Western Blot densitometric data showing compounds having different number of (4-hydroxy-3-methoxy-phenyl)-propenal moieties are capable of reducing Androgen Receptor (AR) expression in human prostate cancer CWR22Rv1 cells. -
FIG. 4 depicts Western Blot images showing newly provided compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing Androgen Receptor (AR) protein expression in human prostate cancer CWR22Rv1 cells. -
FIG. 5 depicts a table showing some selected ASC compounds and monomers are capable of inhibiting proliferation of human prostate cancer cells (LNCaP and CWR22Rv1) stimulated by DHT in vitro. -
FIG. 6 depicts Western Blot data showing four compounds ASC-Q49, ASC-Q103, ASC-JM12, and ASC-JM4, at various concentrations, are capable of reducing endogenous AR expression in LNCaP and CWR22Rv1 human prostate cancer cells. -
FIG. 7 depicts Western Blot data showing compounds ASC-J9 and ASC-JM5 enhances AR protein degradation in the presence of a protein synthesis inhibitor, cycloheximide (CHX), tested in LNCaP cells. -
FIG. 8 depicts two tables (8a and 8b) that summarize the potency of representative ASC compounds in reducing endogenous AR protein expression (using Western Blot analysis) at various concentrations, when tested in LNCaP and CWR22Rv1 human prostate cancer cells. - Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to are incorporated by reference in their entirety, including disclosed structures, formulas, methods of use, methods of treatment, and methods of production. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
- The term “(substituted phenyl)-propenal moiety” as used herein refers to a composition including a phenyl group having attached thereto a propenal moiety (when m equals 1) and an alkoxy or hydroxy moiety, or an alkyl or substituted alkyl moiety. The substitutions may be positioned meta or para or ortho with respect to the propenal moiety as used herein and refers to a general formula
- Where n may be any number of 1, 2, 3 or 4; and m may be any number of 1, 2, 3, 4, or more.
- The term “alkyl” as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g. methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
- The term “alkenyl” as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g. ethenyl, prop-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
- The term “alkenylene” as used herein refers to a straight or branched hydrocarbon chain which contains a carbon-to-carbon double bond and is represented by the formula CnH2n-2, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond or a monovalent substituent, e.g. ethenylene, prop-1-enylene and the like.
- The term “alkoxy” as used herein refers to the radical having the formula —OR wherein R is an alkyl, haloalkyl or cycloalkyl. An “optionally substituted alkoxy” refers to the radical having the formula —OR wherein R is an optionally substituted alkyl as described herein.
- The term “alkynl” as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g. ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.
- The term “aryl” as used herein refers to a radical of carbocyclic ring system wherein at least one of the rings is aromatic. The aryl may be fully aromatic or may contain an aromatic ring in combination with a non-aromatic ring. A “biaryl system” is a compound that includes at least two aryl groups.
- The term “cycloalkyl” as used herein refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- The term “di-ketone bridge”, or “ketone-enol bridge” as used herein refers to a straight or branched hydrocarbon chain including two ketones or an enol positioned in close proximity to a ketone respectively. The “di-ketone bridge” or “ketone-enol bridge” is positioned between at least two aryl moieties.
- The term “hydroxyalkyl” as used herein refers to a straight or branched hydroxy substituted hydrocarbon chain radical having from one to ten carbon atoms, e.g. —CH2OH, —(CH2)2OH and the like.
- The term “androgen” as used herein refers to androgen hormones such as testosterone and dihydrotestosterone (DHT). DHT is the converted product of testosterone by the 5-alpha-reductase enzyme. Androgen stimulates or controls the development and maintenance of masculine characteristics and other physiological functions in vertebrates by binding to androgen receptors, which in turn binds to the androgen/AR-controlled genes (DNA) and activates or modulates the gene.
- The term “androgen receptor” as used herein or “AR” refers to the intracellular receptor that specifically binds androgens, including testosterone and DHT. AR includes all mammalian isoforms, splice variants and polymorphisms of the androgen receptor.
- The term “estrogen receptor” or “ER” or “ER family” as used herein refers to the intracellular receptor specific for estradiol (the main endogenous estrogen). When bound to a hormone, it acts as a transcription factor (it regulates the reading of DNA and production of proteins). ER includes ERα and ERβ. ER includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
- The term “glucocorticoid receptor” or “GR” as used herein refers to the intracellular receptor that has a high affinity to cortisol and other glucocorticoids. GR includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
- The term “progesterone receptor” or “PR” as used herein refers to the intracellular steroid receptor that specifically binds progesterone. PR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- The term “peroxisome proliferator activated receptor” or “PPAR” as used herein refers to all isotypes of PPAR, including PPARα, PPARβ and PPARγ. PPAR increases transcription of target genes by binding to a specific nucleotide sequence in the gene's promoter. When bound to its fatty acid ligand, PPARα forms a heterodimeric complex with the retinoid X receptor (RXR) to regulate transcription. PPARγ is activated by prostaglandins and leukotrienes and regulates the gene expression of proteins involved in the storage of fatty acids. PARβ is weakly activated by fatty acids, prostaglandins, and leukotrienes. Its physiological ligand has not been identified.
- The term “retinoic acid receptor” or “RAR” as used herein refers to the intracellular receptor known to bind many retinoid forms. “RAR” includes all family members, which include RARα, RARβ and RARγ. “RAR” includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- The term “retinoid x receptor” or “RXR” as used herein refers to the intracellular receptor that specifically binds 9-cis-Retinoic acid. “RXR” includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
- The term “steroid receptor” or “steroid nuclear receptor” as used herein refers to intracellular receptors that bind to and regulate the transcription of DNA under the regulation of steroid hormones. Receptors for the different hormones have strong structural and functional similarities which point to an evolution from a common ancestral gene and therefore are considered a gene superfamily. Representative receptors which belong to this gene superfamily include the DNA binding and regulatory proteins controlled by the steroid hormones estradiol (ER), glucocorticoid (GR), androgen (AR), progesterone (PR), mineralocorticoid (MR), the nonsteroid hormones triiodothyronine (T3R) and dihydroxyvitamin D3 (VDR), and two classes of retinoid (all-trans retinoic acid and 9-cis retinoic acid) receptors (RARs and RXRs respectively). More than 32 genes encoding at least 75 proteins with different DNA specificity, regulation, or hormone affinity have been identified as part of this gene superfamily. New members of this superfamily are being reported frequently and are herein intended to be incorporated by reference in their entirety as published in peer reviewed scientific literature or as provided in sequence databases such as GenBank, whether DNA, RNA or polypeptide sequence, and SWISSPROT. Using new biotechnology, molecular biologists and biochemists have identified protein receptors for which the ligands have not yet been identified, thus giving birth to a class of “orphan receptors”. “Steroid receptor” includes all mammalian splice variants and isoforms of the steroid receptors.
- The term “extended release” as used herein refers to dosage form that provides for the delayed, slowed over a period of time, continuous, discontinuous, or sustained release of a compound or composition.
- The term “pharmaceutically acceptable” as used herein refers to approved or approvable by a regulatory agency of the Federal or a state government for use in animals, and more particularly in humans. The term “pharmaceutically acceptable carrier” refers to an approved or approvable diluent, adjuvant, excipient or carrier with which a compound is administered.
- The term “prodrug” as used herein refers to a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. In some but not all instances, the prodrug includes a cleavable ester, which upon cleavage, releases the active form.
- The term “therapeutically effective amount” refers to the amount of a compound that, when administered to a patient for treating a disease or disorder, is sufficient to affect such treatment for the disease or disorder. The “therapeutically effective amount” will vary depending on the compound, the disease or disorder and its severity and the age and weight of the patient to be treated. The “therapeutically effective amount” may include a series of administrations that eventually causes a desired effect whether or not the initial administration is effective.
- The term “derivative” as used herein refers to variations on a core structure or pharmacophore that yields a desired effect. Derivatives may include substitutions along the phenyl ring, the propenal region of the molecule or along a side chain. Thus derivatives encompassed herein include compounds formed from or include at least one disclosed compound, such as those identified in formulas I, II, III, IV, or V. It may be desirable to form derivatives of the particular compounds to modulate solubility, efficacy, aggregation and the like.
- As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972 11:942-944).
- The inventors of the present invention have found that compounds described herein, including those with at least one (substituted phenyl)-propenal moiety show promise for the treatment or prevention of medical conditions. Moreover compounds disclosed herein are believed to possess activities, such as reducing the proliferation of cells that are believed to have or suspected of having a cancerous profile. Additionally, compounds disclosed herein demonstrate the ability to selectively modulate populations of steroid receptors. Thus it is an object of the present invention to provide compounds having biological activities useful in the treatment or prevention of disease in mammals, such as humans.
- The present invention discloses and encompasses a variety of compounds and their derivatives having utility in the areas of medical treatment, such as in the treatment or prevention of medical conditions. Thus compositions disclosed herein may be provided or administered as compounds themselves or may be adapted with a suitable carrier to effect the desired treatment. When providing the compounds disclosed herein as a pharmaceutical, the compounds may be provided in combination with a pharmaceutically acceptable carrier. When providing the compounds disclosed herein as a cosmetic, the compounds may be provided in combination with a cosmetically acceptable carrier. Pharmaceutically acceptable carriers and cosmetically acceptable carriers may be the same, may be derived from one another and the like as known in the pharmaceutical and cosmetic industries, or may be different such as but not limited to variations depending on desired route of administration. Compounds may be tested for solubility, activity and dipole moment before or after the preparation as a pharmaceutical or cosmetic and may be tested alone or in combination with other compounds disclosed herein for synergistic effects. Thus the present invention includes one or more compound and derivatives thereof, including those with hydrophilic or hydrophobic additions, substitutions or subtractions.
- In one aspect of the present invention a compound having at least one (substituted phenyl)-propenal moiety is provided. In some embodiments, compounds having a (substituted phenyl)-propenal moiety have biological activity including anti-androgen/anti-AR biological activity. In one specific embodiment of the present invention the (substituted phenyl)-propenal moiety has the formula according to formula I:
- wherein 1) R3 and R4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl. As can be viewed in the FIGURES (FIGS.), compounds having at least one (substituted phenyl)-propenal moiety are capable of decreasing the presence of the androgen receptor or inducing degradation of the androgen receptor. Moreover compounds having at least one (substituted phenyl)-propenal moiety were shown to reduce cancer cell growth or proliferation of cancer cells. Such inhibition occurred in the presence of a compound capable of cancer cell stimulation. In various nonlimiting embodiments described herein the compound includes a (substituted phenyl)-propenal compound or a pharmaceutically acceptable salt thereof, selected from
monomer - Monomers
- In various embodiments, derivatives of the above referenced monomers having biological activity are also provided. The derivatives may have substitutions at one or more positions to increase one or more characteristic such as activity, solubility and the like. Such derivatives may modulate the dipole moment of a compound and may result in a composition that is more or less hydrophobic or hydrophilic.
- In another aspect of the present invention a compound is provided including a (substituted phenyl)-propenal moiety having the formula according to (Ia) or (IIb):
- wherein: 1) R3, R4, R3, and R4 are independently selected from the group consisting of —H, —OH, and —OCH3; 2) L is a C0-C8 alkylene or L is an unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR1, —CO2R1, —CONR1R2, —NR1R2, —CX3, wherein R1 and R2 are independently selected from the group consisting of —H, —CH3, and —C2H5; 4) X is halogen atom selected from the group consisting of —F, —Cl, and —Br; and further wherein the formula IIa and IIb are the equilibrate tautomers as a common phenomenon of diketone. In some embodiments the compound is selected from the group consisting of II-1, II-2, II-3, II-4 and II-5. The formulas provided as:
- In another aspect of the present invention, a compound is provided according to formula IIc:
- wherein 1) R3, R4, R3 and R4′ are independently selected from the group consisting of —H, —OH, and —OCH3; and 2) R1, and R2 are independently selected from the group consisting of —H, —CH3, —C2H5, a substituted aryl and a substituted benzyl group.
- In another aspect of the present invention, a compound is provided according to formula III:
- wherein R3, R4, R3′, R4′, R3″ and R4″ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen. Nonlimiting examples include those with the formula III-1 or III-2:
- In another aspect of the present invention, a compound is provided according to the formula IV:
- wherein R3, R4, R3′, R4′, R3″, R4″, R3′″, and R4′″ are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen. In one embodiment the compound has the formula IV-1:
- In another aspect of the present invention a compound is provided according to formula V:
- wherein 1) each “n” is independently 1, 2, or 3; 2) R3, R4, R3′, and R4′ are independently selected from the group consisting of —H, —OH, and —OCH3; 3) L-Z side chain can be no-exist, bur if L-Z side chain exists, L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of —H, —OH, an aromatic ring, a cycloalkyl, —COR1, —CO2R1, —CONR1R2, —NR1R2, —CX3; 5) R1 and R2 are independently selected from the group consisting of —H, —CH3, and —C2H5; and 6) X is a halogen atom selected from the group consisting of —F, —Cl, and —Br. In some embodiments the compounds have the formula according to V-1 or V-2. The following are representatives of the compounds with formula V-1 and V-2:
- Synthesis of the disclosed compounds may be performed using standard practices known in the organic synthesis arts using known solvents. Synthesized compounds may be tested for desired activity such as degradation of a steroid receptor, such as the androgen receptor, the ability to prevent or inhibit proliferation of cancer cell lines, the reduction of tumor size in grafted animal studies and the like. Compounds identified as hits or leads may be further adapted using the synthesis methods and techniques disclosed herein. Thus, variations on the provided synthetic methods will be readily apparent to those skilled in the art and are deemed to be within the scope of the present invention.
- Example 1 demonstrates a variety of synthesis schemes for the provided monomers as well as derivatives thereof, which are also encompassed herein. In some embodiments derivatives are provided as a combination of monomers or portions thereof to form a biphenyl, triphenyl, or quadrophenyl ring system or more.
- In many embodiments, a biphenyl ring system was utilized for testing and comparison to other proposed treatments; however compounds having a single (substituted phenyl)-propenal moiety, were also found to have activity such as the ability to prevent proliferation of cancer cell lines stimulated with DHT and the ability to degrade the androgen receptor. Some of the compounds of the present invention were prepared through a condensation of substituted benzaldehydes and 2,4-pentanedione or 3-substituted 2,4-pentanedions by the method known in the literature. Pedersen et al., Liebigs Ann. Chem., 1557-1569 (1985). The desired substituents on the biphenyl ring and on the C4 of the conjugation bridge were synthesized either before or after the condensation. The length of conjugating bridge between the two phenyl moieties could be varied from 5 carbons to 11 carbons through synthetic strategies. Properly adding and removing protecting groups allow ultimate synthesis of disclosed compounds.
- Several analogues and derivatives of compounds having a (substituted phenyl)-propenal moiety have been newly synthesized and evaluated for the anti-androgenic activity. The structure information of some but not all of the disclosed compounds is summarized in
FIG. 2 . - The present invention includes the disclosed compounds themselves, as well as their salts and their prodrugs, if applicable. The salts or prodrugs should retain a portion of the desired biological activity of the parent compound or be provided in a form that the body or subject can convert to a biologically active form. The salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, tartrate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Nonlimiting examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the compounds derivatives described above.
- The compounds of the present invention may be formulated for administration for the prevention or treatment of a variety of medical conditions. Pharmaceutical formulations may include at least one of the disclosed compounds or pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier. Techniques of pharmaceutical production are well known in the art of the present invention and typically include mixing a compound or salt in the presence of a suitable carrier. Suitable carriers for use with the compounds of the present invention include diluents, excipients, or carrier materials, selected according to the intended form of administration and consistent with conventional pharmaceutical or cosmetic practice. Examples of suitable carriers include, but are not limited to, water, physiological saline, phosphate-buffered saline, a physiologically compatible buffer, saline buffered with a physiologically compatible salt, a water-in-oil emulsion, and an oil-in-water emulsion, an alcohol, dimethylsulfoxide, dextrose, mannitol, lactose, glycerin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like, and mixtures thereof. Suitable carriers can also include appropriate pharmaceutically acceptable antioxidants or reducing agents, preservatives, suspending agents, solubilizers, stabilizers, chelating agents, complexing agents, viscomodulators, disintegrating agents, binders, flavoring agents, coloring agents, odorants, opacifiers, wetting agents, pH buffering agents, and mixtures thereof, as is consistent with conventional pharmaceutical practice (“Remington: The Science and Practice of Pharmacy”, 20th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000).
- The pharmaceutical and cosmetic formulations may be provided depending on the desired route of administration using methods known in the pharmaceutical and cosmetic arts. Suitable routes of administration may include oral, intestinal, parenteral, transmucosal, transdermal, intramuscular, subcutaneous, rectal, intramedullary, intrathecal, intravenous, intraventricular, intraatrial, intraaortal, intraarterial, or intraperitoneal administration.
- The pharmaceutical compositions of the present invention can be administered to the subject by a medical device, such as, but not limited to, implantable devices, biodegradable implants, patches, and pumps. Where such a device is used, the compositions may be formulated to include a dissolvable or nondissolvable matrix or medium (for example, a coating, membrane, film, impregnated matrix, polymer, sponge, gel, or porous layer on or within the medical device) to permit the release of the active compound or compounds over a specified period of time.
- For use in a living, whole organism, such as in a human subject, compositions of the present invention can be formulated and provided in any formulation suitable to the intended form of administration and consistent with conventional pharmaceutical practice (“Remington: The Science and Practice of Pharmacy”, 20th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000). Examples of suitable formulations include tablets, capsules, syrups, elixirs, ointments, creams, lotions, sprays, aerosols, inhalants, solids, powders, particulates, gels, suppositories, concentrates, emulsions, liposomes, microspheres, dissolvable matrices, sterile solutions, suspensions, or injectables, and the like. Injectables can be prepared in conventional forms either as liquid solutions or suspensions, as concentrates or solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- Compounds of the present invention were tested for their effect on steroid receptors and their effect on cancer cell populations. It was found that compounds of the present invention were able to reduce androgen receptor expression (see
FIGS. 3 and 4 ). Further investigation demonstrated that compounds of the present invention were able to inhibit cancer cell growth (seeFIG. 5 ) and reduce expression of the androgen receptor within cancer cells (seeFIGS. 6 and 8 ). The inventors also considered potential mechanisms of action or potential pathways.FIG. 7 supports the inventors' beliefs that the compounds of the present invention induce degradation of the androgen receptor. Thus the activities demonstrated herein support therapeutic or prophylactic treatment against medical conditions such as a variety of cancers and androgen associated disorders. - The present invention includes methods of treating, ameliorating symptoms from or preventing the progression of a variety of medical conditions using the disclosed compounds and compositions, including pharmaceutical and cosmetic formulations. The medical conditions may, at least in part, be modulated by a steroid receptor. Steroid receptors of particular interest may include but are not limited to androgen receptor (AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptors (RARs and RXRs), and orphan steroid hormone receptors. Compositions or compounds of the present invention may target a specific receptor, such as the androgen receptor or may target particular receptors within the steroid receptor superfamily.
- The methods of the present invention may prevent, treat or ameliorate symptoms from cancers such as but not limited to prostate cancer, liver cancer, bladder cancer, cervical cancer, lung cancer and breast cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, endometrial cancer, ovarian cancer, central nervous system cancer, and the like. The methods of the present invention may induce cytotoxicity against tumor cells or may inhibit tumor cell growth. Determining whether a compound or pharmaceutical is beneficial for the treatment or prevention of a particular disease may include testing the compounds or their derivatives in vitro, in vivo in an animal model or with a cell-based assay on a suitable cell line. In the instance of cancer, cell lines having a profile of a cancerous cell, such as cell lines prepared from cancer cells, may be utilized. In some embodiments activities of compounds of the present invention are evaluated for the ability to inhibit cancer cell growth or proliferation, optionally stimulated with a stimulator, such as DHT. Compounds disclosed herein were specifically shown to reduce growth or proliferation of prostate cancer cells.
- In other embodiments, the compounds their derivatives, pharmaceutical compositions and the like are used to prevent, treat or ameliorate symptoms from neurological and neuromuscular disorders such as Kennedy Disease. Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a gender-specific motor neuron disease that affects 1 in every 40,000 males (reviewed by Katsuno et al., 2004). SBMA patients have a mutated androgen receptor containing an expanded polyglutamine tract. The expanded polyglutamine androgen receptor forms aggregates that interfere with cell functioning and is the factor that causes the proximal muscle atrophy associated with SBMA. The methods of the present invention may include relieving the stress caused by aggregate formation by reducing the amount of the mutant AR to a level that could be more easily policed by the cells' native housekeeping machinery. The methods of the present invention may including selectively degrading the androgen receptor and thus may be used as a therapy for SBMA. The disclosed compounds that can enhance androgen receptor degradation may suppress the steady-state level of the receptor thus, attenuating the severity of aggregate formation in patients.
- Compounds and compositions of present invention may prevent, treat or ameliorate symptoms from androgen related hair disorders. For example, androgenetic alopecia or “male pattern baldness” is hair loss caused by androgen activity on the androgen receptors in follicles and adjacent cells. As another example, hirsutism is excessive growth of thick dark hair in locations where hair growth in women usually is minimal or absent. Such male-pattern growth of terminal body hair usually occurs in androgen-stimulated locations, such as the face, chest, and areolae. Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention.
- Compounds and compositions of the present invention may treat inflammation (e.g., rheumatoid arthritis), acne, alopecia, and may accelerate wound healing. Acne is caused by androgen-induced AR activation of sebaceous glands and may therefore be treated by administering a compound capable of preventing or decreasing AR activation. Compounds of the present invention are believed to induce degradation of the androgen receptor and thus would provide an effective treatment against such medical conditions. Androgenetic alopecia and other hair growth disorders are known to cause by the activation of androgen receptors (AR) in hair follicles by endogenous androgen. Certain inflammation conditions and wound healing are also believed to be associated with the androgen receptor in response to androgen. Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention. Topical application of such formulations may be of particular interest.
- Compounds and compositions of the present invention may be used in the treatment of endocrine disorders. Androgen excess is one of the most common endocrine disorders in women (reviewed by Bulun and Adashi, 2003). This pathophysiological status can be found in women with various endocrine disorders, including polycystic ovary syndrome (PCOS), pituitary adenoma-induced hyperprolactinemia, Cushing's syndrome, congenital adrenal hyperplasia, non-classical adrenal hyperplasia, ovary or adrenal tumor, and iatrogenic androgen excess. Among these disorders, PCOS, occurring in 5-10% of reproductive-age women, is the most frequently identified cause of hyperandrogenism. Recently, a relative increase in the ratio of circulating androgens to circulating estrogens (named as androgenicity) has been observed in post-menopausal women (Lee et al., 2004). Androgenicity is the consequence of a greater decrease in estradiol and estrone synthesis than that of androgen synthesis after menopause, and its clinical implications are under active study. It has been shown that women exhibiting androgenicity are more frequently seen with central obesity (Peohlman et al., 1995). Fat deposit in the abdominal wall is metabolically active and is associated with insulin resistance in the peripheral tissues (Evans et al., 1983). Other than the above-mentioned endocrine disturbances, hyperandrogenic symptoms can also be detected in human immunodeficiency virus (HIV)-infected women showing lipodystrophy syndrome (Hadigan et al., 2000). It has been suggested that hyperandrogenism may be involved in lipid aberrations observed in the latter group of patients.
- The methods of the present invention include the treatment of a variety of medical conditions as disclosed herein or are believed to be associated at least in part with a steroid or steroid associated disorder. The methods of treatment include administering a compound, pharmaceutical formulation or cosmetic formulation of the present invention to an individual or subject in need thereof. Subjects may be treated with a therapeutically effective dosage. A therapeutically effective dosage may vary somewhat from compound to compound, patient to patient, and will depend on the condition of the patient and route of delivery. As general guidance, a dosage from about 0.1 to about 50 mg/kg may have therapeutic efficacy, while still higher dosages potentially being employed.
- Many of the features of the present invention are explained in greater detail in the following non-limiting examples. Thus the following examples are provided to further illustrate the various aspects and embodiments of the present invention. It is be understood; however, that the invention as fully described herein and as recited in the claims is not intended to be limited by the details of the following examples.
- In some embodiments, compounds composed of a single (substituted phenyl)
- propenal core structural unit (monomers) were prepared through standard and advanced organic syntheses. In some embodiments, compounds consisting of two or more (substituted phenyl) propenal core structural moieties were prepared by a condensation of substituted benzaldehydes and 2,4-pentanedion or 3-substituted 2,4-pentanedions by the method known in the literature. Pedersen et al (Liebigs Ann. Chem., 1557-1569, 1985). The desired substituents on the biphenyl ring and on the C4 of conjugation bridge were synthesized either before or after the condensation. The length of conjugation bridge between the two phenyl moieties could be varied from 5 carbons to 11 carbons through synthetic strategies. Properly adding and removing protecting groups allow ultimate synthesis of the disclosed derivatives. In addition, various synthetic steps may be performed in an alternate sequence in order to give the desired compounds.
- Derivative phosphate prodrugs were further prepared by reacting compounds having compounds a (substituted phenyl)-propenal moiety with phosphorous oxychloride in an appropriate solvent, e.g., dichloromethane, in the presence of an organic base, e.g., triethylamine. Tartrate of disclosed compounds as water-soluble salts were synthesized by reacting compounds having a (substituted phenyl)-propenal moiety with tartaric acid in water.
- Melting points were determined on a Fisher-John melting point apparatus and are uncorrected. Proton Nuclear Magnetic Resonance (1H NMR) and 13C NMR spectra were measured on Varian Gemini 300 or Inova 500 spectrometers with tetramethylsilane (TMS) as the internal standard. 31P NMR was conducted on 500 MHz Varian Inova spectrometer using phosphoric acid as external standard. Chemical shifts are reported in δ (ppm). Mass spectra (MS) were obtained on an Agilent 1100 series LC-MSD-Trap or PE-Sciex API-3000 spectrometers. Flash column chromatography was performed on silica gel (100-200 mesh) or alumina (aluminum oxide, basic, Brockmann I, standard grade, ˜150 mesh). HPLC was conducted on Shimadzu SCL 10A instrument. HPFC was conducted on a Biotage system or ISCO Inc. Chemflash chromatographic system. Preparative thin layer chromatography (PTLC) on silica gel plates (Kieselgel 60, F254, 1.00 mm) were also used for separation and purification. Precoated silica gel plates (Kieselgel 60, F254, 0.25 mm) were used for thin layer chromatography (TLC) analysis. ASC-J9 was synthesized as starting material by reaction of 3,4-dimethoxybenzaldehyde with 2,4-pentanedione based on a published method (Pedersen et al., Liebigs Ann. Chem., 1557-1569, 1985).
- The monomers, structurally with a (3,4-dimethoxy or 3-methoxy, 4-hydroxy substituted phenyl)-propenal moiety, a basic structure of the currently provided compounds, have been synthesized by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid with corresponding reagents (
monomers 1, 3), or reaction of 3,4-dimethoxy-benzaldehyde or 3-methoxy-4-hydroxy benzaldehyde with ethyl levulinate (monomers 5 and 6). Monomor-7 was synthesized starting from 3-(3,4-dimethoxyphenyl)propane through two steps. More specifically, the synthesis methods for the monomers are described as below and illustrated inScheme 1. -
Monomer 1,3-(3′,4′-Dimethoxy-phenyl)-acrylic acid methyl ester, was synthesized by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid with methanol in the presence of acetic chloride. After refluxing for 2.5 h, the reaction mixture was concentrated by evaporation to ⅓ and the white solid was filtered and dried in vacuo to get the desired product in 76% yield as a white crystalline solid. mp. 74-75° C. ESI MS m/z: 223.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64 (d, 1H, J=15.9 Hz, H-3), 7.11 (dd, 1H, J=6.9, 2.1 Hz, H-6′), 7.05 (d, 1H, J=2.4 Hz, H-2′), 6.85 (d, 1H, J=8.4 Hz, H-5′), 6.32 (d, 1H, J=15.9 Hz, H-2), 3.92 (s, 6H, phenyl OCH3), 3.80 (s, 3H, ester OCH3). -
Monomer 3, a mixed anhydride, was prepared by reaction of 3-(3′,4′-Dimethoxy-phenyl)-acrylic acid in toluene/CH2Cl2 (1:1) in the presence of Et3N. The solution was cooled to 0° C., ethyl chloroformate (1.5 eq.) was added dropwise. After stirring at 0° C. for 2 h, the precipitate was filtered out. The filtrate was concentrated to get a relatively pure white solid, which was purified by a fast filtration through a thin silica gel pad and eluted with hexanes:ethyl acetate (1:0 to 4:1) to afford the desired product as a white solid in quantity. ESI MS m/z: 281.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.78 (d, 1H, J=15.9 Hz, H-3), 7.15 (dd, 1H, J=8.4, 1.8 Hz, H-6′), 7.06 (d, 1H, J=1.8 Hz, H-2′), 6.89 (d, 1H, J=8.4 Hz, H-5′), 6.29 (d, 1H, J=15.9 Hz, H-2), 4.37 (q, 2H, J=6.9 Hz, OCH 2CH3), 3.92 (d, 6H, J=1.2 Hz, phenyl OCH3), 1.40 (t, 3H, J=7.2, OCH2CH3). -
Monomer 5, i.e., 6-(3′,4′-Dimethoxy-phenyl)-4-oxo-hex-5-enoic acid ethyl ester, was synthesized by reaction of 3,4-dimethoxy-benzaldehyde with ethyl levulinate as shown inScheme 1. Ethyl levulinate (1 eq.) reacted with boron oxide (0.7 eq) in ethyl acetate at 40° C. for 30 min. To the resulting mixture tributyl borate and 3,4-dimethoxy-1-benzaldehyde (both 1 eq.) were added and the mixture was stirred at 40-42° C. for 30 min. A solution of butyl amine (0.7 eq) in ethyl acetate was added slowly and the mixture was further allowed to stir at 40-42° C. overnight. 5% hydrochloride acid (1.3 eq) was added and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to r.t. and was partitioned. The aqueous portion was extracted with ethyl acetate twice. The combined ethyl acetate extract was washed with water topH 4 and dried over MgSO4. After filtration and concentration, the crude was purified by PTLC to givemonomer 5 as white solid. mp. 62-63° C. ESI MS m/z: 293.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.55 (d, 1H, J=16.2 Hz, H-6), 7.14 (dd, 1H, J=9.0, 2.1 Hz, H-6′), 7.08 (d, 1H, J=1.8 Hz, H-2′), 6.88 (d, 1H, J=8.4 Hz, H-5′), 6.65 (d, 1H, J=16.2 Hz, H-5), 4.16 (q, 2H, J=6.9 Hz, OCH 2CH3), 3.93 (s, 6H, phenyl OCH3), 3.01 (t, 2H, J=6.6 Hz, H-3), 2.69 (t, 2H, J=6.6 Hz, H-2), 1.27 (t, 3H, J=6.9, OCH2CH 3). -
Monomer 6,6-(4-Hydroxy-3-methoxy-phenyl)-4-oxo-hex-5-enoic acid ethyl ester, was synthesized by reaction of vanillin with ethyl levulinate with a similar method recorded in the synthesis ofMonomer 5. The desired compound was obtained as a yellow crystalline solid. mp. 55-56° C. ESI MS m/z: 279.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.54 (d, 1H, J=15.0 Hz, H-6), 7.12-7.06 (m, 2H, aromatic-H), 6.94 (d, 1H, J=8.1 Hz, aromatic H-5′), 6.63 (d, 1H, J=15.0 Hz, H-5), 4.16 (q, 2H, J=7.2 Hz, OCH 2CH3), 3.94 (s, 3H, phenyl OCH3), 3.01 (t, 2H, J=6.9 Hz, H-3), 2.69 (t, 2H, J=6.9 Hz, H-2), 1.27 (t, 3H, J=7.2, OCH2CH 3). -
Monomer 7, i.e., 7-(3,4-Dimethoxy-phenyl)-hept-6-ene-2,5-dione was made by 3-(3,4-dimethoxyphenyl)propane through 2 steps. 3,4-dimethoxycinnamaldehyde was made as described in the synthesis of Q110 (Scheme 13) in 60% yield. Dissolving the resulting compound (1 eq.) in dry EtOH, 3-butene-2-one (1 eq.) was added. The reaction solution was heated to 80° C. under N2, 3-Benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazoliumchloride (0.1 eq.), TEA (0.4 eq.) in EtOH was added dropwise. The resulting reaction mixture was stirred at the temperature for 10 h, then evaporated to get a yellow oily residue. The crude was dissolved in CH2Cl2 and washed with 0.5% H2SO4, 2% NaHCO3, and brine. After drying over Na2SO4, the crude was purified by chromatography though an Al2O3 flash column, followed by crystallization from ethyl ether and pentane to afford the target compound as an off-white solid. mp. 71-73° C. ESI MS m/z: 263.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.55 (d, 1H, J=16.2 Hz, H-6), 7.14 (dd, 1H, J=9.9, 2.1 Hz, H-6′), 7.08 (d, 1H, J=1.8 Hz, H-2′), 6.88 (d, 1H, J=8.4 Hz, H-5′), 6.64 (d, 1H, J=16.2 Hz, H-5), 3.93 (s, 6H, phenyl OCH3), 2.98 (t, 2H, J=6.0 Hz, H-3), 2.83 (t, 2H, J=6.0 Hz, H-3), 2.24 (s, 3H, COCH 3). - In order to study the effect of C4-subtitution of the compounds on AR activity, a verity of C4-substituted compounds with different functional groups (e.g., hydroxyl, ester and amide, etc) were synthesized. These compounds were prepared by treatment of 1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one (ASC-J9), synthesized through the method described in
Scheme 2 with an appropriate bromide or chloride compound (or with ethylene oxide as an alternative for making compound Q9) in basic condition. - Compounds Q9 was synthesized as follows. To a 1N NaOH aqueous solution (0.2 mL, 0.2 mmol) containing 0.1 mmol of tetrabutylammonium bromide (phase transferring catalyst, PTC) was added ASC-J9 (0.1 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at room temperature for 10 min and 2-bromoethane alcohol (0.2 mmol) or ethylene oxide (25 mmol) was added. The resulting reaction mixture was stirred at 40° C. overnight for compound Q9. The two layers were separated, and the aqueous was extracted with CH2Cl2 3 times. The combined organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by PTLC and recrystallized from EtOAc. Analytical data for compound Q9 is shown bellow.
- Compound Q9: Yellow crystalline solid (EtOAc), mp. 149-150° C. ESI MS m/z: 441.3 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.63 (d, 1H, J=15.9 Hz, H-1), 7.53 (d, 1H, J=15.9 Hz, H-7), 7.14-7.04 (m, 4H, aromatic ring H), 6.88-6.85 (2H, aromatic ring H), 6.65 (d, 1H, J=15.9 Hz, H-2), 6.31 (d, 1H, J=15.9 Hz, H-6), 4.29 (t, 2H, J=12, and 6 Hz, CH2 CH 2H), 3.94-3.88 (12H, OCH3), 2.84-2.79 (t, 1H, C4-H), 2.14-2.10 (m, 2H, CH 2CH2OH).
- Compounds Q44, Q49, Q77 were synthesized by reacting ASC-J9 in CH2Cl2 or THF with an appropriate bromide or chloride compound in the presence of K2CO3 and Cs2CO3 (9:1) or NaH as shown
scheme 2. For the examples of making compounds Q49 and Q77. To a solution of NaH (4 eq.) in THF was added ASC-J9 (1 eq.) at 0° C. The resulting solution was stirred at 0° C. for 0.5 h then room temperature for 1.5 h. 2-Chloride-N,N-diethylacetamide (4 eq.) (for Q49) or 2-Chloride-N,N-dimethylacetamide (4 eq.) (for Q77) were added. The resulting mixture was heated to reflux overnight. The reaction mixture was cooled to r.t. (room temperature), diluted with EtOAc, and washed with 10% H2SO4 aq. The organic layer was further washed with sat. NaHCO3, H2O and brine, and dried over Na2SO4. The desired product was purified by flash column chromatography and crystallized from EtOAc. - Compound Q49: Yellow crystalline solid, mp. 166-167° C. ESI MS m/z: 510.7[M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.68 (d, 2H, J=−15.9 Hz, H-1, 7), 7.16-7.06 (4H, aromatic ring H), 6.87-6.84 (2H, aromatic ring H), 6.80 (d, 2H, J=15.9 Hz, H-2, 6), 4.97 (t, 1H, J=12.0 and 6.0 Hz, C4-H), 3.92-3.89 (12H, OCH3), 3.43-3.33 (m, 4H, CH2CON(CH 2CH3)2), 3.04 (d, 2H, J=6.6 Hz, C4-CH 2CON(CH2CH3)2), 1.24 (t, 3H, CH2CON(CH2CH 3)2), 1.09 (t, 3H, CH2CON(CH2CH 3)2).
- Compound Q77: Yellow crystalline solid, mp. 155-157° C. ESI MS m/z: 482.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.68 (d, 2H, J=15.6 Hz, H-1, 7), 7.16-7.06 (4H, aromatic ring H), 6.87-6.83 (2H, aromatic ring H), 6.77 (d, 2H, J=15.6 Hz, H-2, 6), 4.92 (t, 1H, J=13.5 and 6.6 Hz, C4-H), 3.92-3.88 (12H, OCH3), 3.09-3.04 (m, 5H, —CH 2CO and N(CH 3)), 2.94 (s, 3H, N(CH 3)).
- Compounds Q50 and Q98 were synthesized to compare their activity with Q44 and Q49 (Scheme 3). To a solution of 5-Hydroxy-1,7-bis-(4-hydroxy-3-methoxy-phenyl)-hepta-1,4,6-trien-3-one and 3,4-dihydro-2H-pyran (20 eq.) in dry dichloromethane was added pyridinium chlorochromate (PPTS) (0.1 eq.). The resulting solution was stirred at r.t. for 48 h. The solution was then washed with water. The solvent was removed and the resulting compound was purified on Biotage column chromatography. Reaction of the obtained product (Q1) with ethyl bromoacetae (Q50) or 2-Chloride-N,N-diethylacetamide (4 eq.) (Q98) in the presence of K2CO3 and Cs2CO3 (9:1) then removal of THP protecting group by PPTS/EtOH gave the desired products Q50 and Q98 respectively.
- Compound Q50: Amorphous. mp. 63-65° C. ESI MS m/z: 455.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.65 (d, 2H, J=15.9 Hz, H-1, 7), 7.19-7.04 (6H, aromatic ring H), 6.72 (d, 2H, J=15.9 Hz, H-2, 6), 4.16 (2H, COOCH 2CH3), 3.96-3.92 (6H, OCH3), 3.04 (d, 2H, J=7.2 Hz, C4-CH 2COOCH2CH3), 1.27-1.23 (3H, COOCH2CH 3).
- Compound Q98: Amorphous. mp. 68-71° C. ESI MS m/z: 482.10 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.65 (d, 2H, J=15.9 Hz, H-1, 7), 7.12-7.03 (4H, aromatic ring H), 6.94-6.89 (2H, aromatic ring H), 6.76 (d, 2H, J=15.9 Hz, H-2, 6), 4.96 (t, 1H, J=13.2 and 6.9 Hz, C4-H), 3.92-3.89 (6H, OCH3), 3.44-3.33 (m, 4H, CH2CON(CH 2CH3)2), 3.04 (d, 2H, J=6.6 Hz, C4-CH 2CON(CH2CH3)2), 1.25 (t, 3H, CH2CON(CH2C/H 3)2), 1.10 (t, 3H, CH2CON(CH2CH 3)2).
- This compound was synthesized starting from a commercially available substituted benzaldehyde with 4-acetyl-5-oxohexanoate as shown in
Scheme 4. - More specifically, 4-acetyl-5-oxohexanoate was reacted with boron oxide (0.7 eq) in ethyl acetate at 40° C. for 30 min. To the resulting mixture tributyl borate and 3-methyl-4-hydroxy benzaldehyde (both 1.6-1.8 eq) were added and the mixture was stirred at 40-42° C. for 30 min. A solution of butyl amine (1.5 eq) in ethyl acetate was added slowly and the mixture was further allowed to stir at 40-42° C. overnight. 10% hydrochloride acid (2.5 eq) was added and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to r.t. and partitioned. The aqueous portion was extracted with ethyl acetate twice. The combined ethyl acetate extract was washed with water to pH ˜4 and dried over MgSO4. After filtration and concentration, the crude was purified by silica gel column chromatography (HPFC) with hexanes:ethyl acetate as eluent and crystallized from ethyl acetate.
- Synthesis of compounds: Q30, Q35, and Q70
- To study the function of di-ketone group in AR activity, a series of compounds with an imine group replacing one of ketones were synthesized.
- Compounds Q30, Q35 were synthesized by reaction of ASC-J9 with appropriate amines in the presence of BF3.OEt2 (Scheme 5). For example, to a solution of ASC-J9 in 1,2-dichloroethane, N,N-diethylamine (compound Q30) (1.2 eq.) was added. The resulting solution was cooled to −30° C. and fresh BF3.OEt2 (2 eq.) was added dropwise. The mixture was stirred under nitrogen at −30° C. to room temperature with TLC monitoring. After quenching with the addition of pyridine (approximately 3 eq.) the mixture was washed with brine and dried over MgSO4. Evaporation of the solvent and purification with flash column chromatography yielded the desired product Q30. ESI MS m/z: 452.4 [M+H]+.
- Compounds Q70 was synthesized by reaction of ASC-J9 (0.75 mmol) with (R)-(−)-2-phenylglycinol (1.16 mmol) in anhydrous toluene as shown in the
scheme 5. The reaction mixture was heated to reflux with a Dean-Stark trap overnight. The solvent was evaporated, and ethyl acetate was added and re-evaporated. The obtained crude was purified by column chromatography on Biotage system to afford the desired product Q70 as a light yellow solid. ESI MS m/z: 516.4 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.54 (d, 1H, J=15.6 Hz, H-1), 7.40-7.28 (5H, aromatic ring H), 7.13 (d, 1H, J=15.9 Hz, H-6), 7.16-7.09 (2H, aromatic ring H), 6.95-6.80 (4H, aromatic ring H), 6.68 (d, 1H, J=15.6 Hz, H-2), 6.63 (d, 1H, J=15.9 Hz, H-7), 5.63 (s, 1H, C4-H), 3.94-3.83 (m, 15H). - Synthesis of compounds: Q99, Q106, Q113, JM2, and JM20.
- In the continually exploring the effects of C4 side chain on AR activity, a series of compounds with a carbonyl group containing C4-substitutions were synthesized. Compound Q99 was synthesized by reaction of ASCJ-9 with 3-Chloro-2-methoxymethoxy-propene, followed by removal of methoxymethyl group as showed in
Scheme 6. More specifically, an aqueous solution of NaOH (2 eq.) and tetrabutylammonium bisulfate (TBABS) was stirred for 5 min. To the reaction solution was added a solution of ASCJ-9 (1 eq.) in 1,4-dioxane dropwise at rt and the resulting red two phased-mixture was stirred at rt. for 10 min. To this mixture was added 3-Chloro-2-methoxymethoxy-propene (1.5 eq) in 1,4-dioxane and the resulting solution was stirred at rt. for 5 min then at 70° C. overnight. The solid was removed by filtration and the filtrate was concentrated to dryness. The resulting residue was suspended in 1% H2SO4/dioxane (2:1, volume) and the suspension was stirred at rt. for 4 h with TLC monitoring. The reaction mixture was extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography and eluted with hexanes/EtOAc mixture to give the desired product as a yellow crystalline solid. M.p. 163-166° C. ESI MS m/z: 453.1 [M+H]+. - Compounds Q106 and Q113 was synthesized with the method described for making the compound Q44 in
Scheme 2. An example to make Q106 was described as below. To a solution of ASC-J9 (0.25 mmol) in dry CH2Cl2 (5 mL) was added 2-bromo-1-phenyl-ethanone (1.2 eq.), K2CO3/Cs2CO3 (10:1) (˜2 eq.). The reaction mixture was stirred at rt overnight with TLC monitoring. The reaction mixture was diluted with EtOAc and washed with H2O, then dried over Na2SO4. The obtained crude was purified by silica gel flash column chromatography eluted by hexanes and EtOAc mixture to get the desired product. - Compounds Q106, yellow crystal, mp. 160-2° C. ESI MS m/z: 515.2 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 8.14-8.01 (2H, aromatic ring H), 7.74-7.68 (2H, H-1, 7), 7.65-7.46, (m, 4H, aromatic ring H), 7.18-7.15 (1H, aromatic ring H), 7.09-7.06 (2H, aromatic ring H), 6.91-6.80 (m, 4H, aromatic ring H), 6.69 (d, 2H, J=15.3 Hz, H-2, 6), 3.92-3.90 (12H, OCH3), 3.78 (2H, —CH 2CO).
- Compounds Q113, yellow fluffy solid, mp. 145-7° C. ESI MS m/z: 479.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 7.75 (d, 1H, J=15.3 Hz, H-1, 7), 7.20-7.17 (2H, aromatic ring H), 7.07-7.06 (2H, aromatic ring H), 6.90, 6.88 (2H, aromatic ring H), 6.86 (1H, J=15.3 Hz, H-2, 6), 3.95-3.93 (12H, OCH3), 3.76 (2H, —CH 2CO), 2.14-2.05 (m, 1H, cyclopropyl-H), 1.10-1.04 (m, 2H, cyclopropyl-H), 0.93-0.86 (m, 2H, cyclopropyl-H).
- Compound JM2 was synthesized by reaction of ASC-J9 (40 mg) with iodoacetamide (80 mg) and anhydrous sodium carbonate (40 mg) in dry acetone as showed in
Scheme 7. The reaction mixture was heated to reflux for 24 hours. After cooling, the mixture was filtered to remove inorganic solid and filtrate was evaporated. The obtained crude residue was purified by preparative silica gel chromatography plate (Ethyl acetate only) to afford the desired product as a light yellow solid. - Compound JM2, amorphous; ESI MS m/z: 452.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.79 (d, 2H, J=15.3 Hz, H-1, 7), 7.4-6.4 (6H, aromatic ring H), 6.33 (d, 2H, J=15.3 Hz, H-2, 6), 3.93, 3.92 (all s, both 6H, OCH 3), 2.06 (d, J=6.3 Hz, 2H, CH 2CONH2).
- Synthesis of JM-10. A mixture of 1.0 gram of ASC-J9, 5 ml of acetic anhydride, and 1 ml of trimethyl orthoformate was stirred at 70° C. for 22 hours (Scheme 7). The solution was then vacuum evaporated to dryness. The residue was re-dissolved in CH2Cl2-ethanol to re-crystallize. Compound JM10 was afforded as orange-reddish crystals (270 mg); mp. 137-138° C.; ESI MS m/z: 425.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 10.37 (s, 1H, C4-COH), 7.94, 7.71 (both d, 2H each, J=15.6 Hz, H-1, 2, 6, 7), 7.26 (dd, 2H, J=1.8, 8.7 Hz, aromatic 5′-H), 7.17 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.91 (d, 2H, J=8.7 Hz, aromatic 6′-H), 3.97, 3.95 (both s, 6H each, OCH3).
- Synthesis of compound Q100, Q101, JM1, JM6, and JM7.
- Compounds Q100, Q101, JM1, JM6, and JM7 were made with an unsaturated side chain at C4 position of ASC-J9 intending to enhance anti-prostate cancer activity. Compound Q100 was synthesized by reaction of ASC-J9 with 3-bromo-propyne in CH2Cl2 at 60° C. over night in the presence of K2CO3. Compound Q101 was made by reaction of ASC-J9 with bromopropene in DMF at 100° C. for 2 h in the presence of K2CO3 and KI (Scheme 8). The crude compounds were purified by silica gel flash column chromatography eluted by hexanes and EtOAc mixture to get the desired products.
- Compound Q100, yellow solid amorphous, mp. 75-78° C. ESI MS m/z: 453.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 7.75 (d, 1H, J=15.3 Hz, H-1), 7.69 (d, 1H, J=15.6 Hz, H-7), 7.23-7.05, and 6.91-6.85 (m, 7H, aromatic ring H and H-2), 6.73 (1H, J=15.6 Hz, H-6), 3.96-3.91 (12H, OCH3), 3.46 (1H, C4-H), 2.96 (s, 1H, acetylene), 2.94-2.90 (dd, 2H, —CH 2CCH).
- Compound Q101, amorphous, mp. 69-72° C. ESI MS m/z: 437.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 7.71 (d, 1H, J=15.6 Hz, H-1), 7.70 (d, 1H, J=15.6 Hz, H-7), 7.18-7.12 (m, 2H, aromatic ring H), 7.06-7-7.00 (m, 2H, aromatic ring H), 6.90-6.85 (2H, aromatic ring H), 6.85 (1H, J=15.6 Hz, H-2), 6.67 (1H, J=15.6 Hz, H-6), 5.64-5.49 (m, 1H, ethylene H), 5.19-5.07 (m, 2H, ethylene H), 3.94-3.91 (m, 12H, OCH3), 296 (d, 2H, —CH 2—).
- Compound JM1 was synthesized by reaction of ASC-J9 (40 mg) with cinnamyl bromide and anhydrous sodium carbonate in dry acetone (Scheme 9). The reaction mixture was heated to reflux for 24 hours. After cooling, the mixture was filtered to remove inorganic solid and filtrate was evaporated. The obtained crude was purified by preparative silica gel chromatography plate (n-Hexane-Ethyl acetate=1:1) to afford the desired product JM1 as a light yellow solid. Amorphous; ESI MS m/z: 513.4 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.74 (d, 2H, J=15.3 Hz, H-1, 7), 7.32 (d, 1H, J=18.6 Hz, —CH2CH═CH—), 7.4-6.4 (11H, aromatic ring H), 6.93 (d, 2H, J=15.3 Hz, H-2, 6), 6.46 (d, 1H, J=18.6 Hz, —CH2CH═CH—), 3.91, 3.88 (all s, both 6H, OCH 3), 3.50 (br d, 2H, —CH2CH═CH—).
- Compound JM6 was synthesized by reaction of ASC-J9 (60 mg) with bromomethyl acetate (50 mg) and sodium hydroxide (20 mg) in dry acetone (Scheme 9). The reaction mixture was heated to reflux for 24 hours. After cooling, the mixture was filtered to remove inorganic solid and filtrate was evaporated. The obtained crude was purified by preparative silica gel chromatography plate (n-Hexane-Ethyl acetate=1:2) to afford the desired product JM6 as a light yellow solid (ESI MS m/z: 467.3 [M+H]+).
- Compound JM7, obtained as a by-product of JM4 aforementioned, yellow fine crystals from EtOAc/hexanes; mp. 109-110° C.; ESI MS m/z: 545.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.83 (s, 1H, CH═C— at C4), 7.79, 7.51, 6.98, 6.83 (all d, 1H each, J=15.5 Hz, H-1, 2, 6, 7), 7.20, 7.15, 7.08 (all dd, 1H each, J=1.8, 8.4 Hz, aromatic 5′-H), 6.87 (d, 1H, J=8.4 Hz, aromatic 6′-H), 6.83 (d, 2H, J=8.4 Hz, aromatic 6′-H), 7.07, 7.06, 6.99 (all d, 1H each, J=1.8 Hz, aromatic 2′-H), 3.92, 3.88 (all s, 6H each, OCH3), 3.90, 3.83 (all s, 3H each, OCH3).
- Synthesis of compounds: Q102-Q104, Q108, Q114-Q115, JM12-JM14, and JM16-JM19.
- Compounds Q102-Q104, Q108, JM12-JM14, JM17 were synthesized to evaluate the properties of the C4-alkyl substitution on ASC-J9 with differences in chain length, in ring size, and in functional groups at chain-end (e.g., Q108 and JM14). Compounds Q114-Q115, JM16, JM18-19 were synthesized to evaluate the functions of not only the C4-side chain but also the substitutions on the bi-phenyl moiety. All compounds were prepared by reaction of 2,4-pentadione with appropriate alkyl or alkylene (or substituted alkyl or alkylene) bromide or iodine in benzene with DBU as a base. The resulting product 3-substituted 2,4-pentadione further reacted with 3,4-dimethoxybenzaldehyde or 4-methoxybenzaldehyde or 3-methoxy-4-hydroxybenzaldehyde to afford the desired products (Scheme 10). An example to make Q104 was illustrated as below.
Mix 2,4-pentadione 0.2 g (2 mmol) andDBU 30 ul (1 eq.) inbenzene 3 mL. To this solution was added dropwise 0.48 g (1 eq.) of octyl iodine in 1 mL of benzene at r.t. The resulting solution was stirred at r.t. overnight. The reaction mixture was washed with brine and extracted the CH2Cl2, dried over Na2SO4 and purified by silica gel flash column chromatography to give a mixture of C3-octanyl substituted 2,4-pentadione and O-octyl substituted 2,4-pentadione. Reaction of the mixture with 3,4-methoxybenzaldehyde through the method mentioned above afforded the compound Q104. - Compound Q104, yellow solid from EtOAc/hexanes (2:1), mp. 87-90° C. ESI MS m/z: 509.3 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.71 (d, 1H, J=15.6 Hz, H-1), 7.63 (d, 1H, J=15.9 Hz, H-7), 7.21-7.14 (m, 2H, aromatic H), 7.08-7.05 (m, 2H, aromatic H), 6.95 (d, 1H, J=15.6 Hz, H-2), 6.91-6.84 (m, 2H, aromatic H), 6.73 (d, 1H, J=15.9 Hz, H-6), 3.94-3.91 (m, 12H, —OCH3), 2.55 (t, 1H, H-4), 1.61-1.22 (m, 12H, butyl group), 0.87 (m, 3H, —CH3).
- Compound Q102, a red needle crystal from EtOAc/hexanes, mp. 162-164° C. ESI MS m/z: 425.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.73 (d, 2H, J=15.3 Hz, H-1, 7), 7.23-7.19 (dd, 2H, J=8.1, 1.8 Hz, aromatic H), 7.09 (d, 2H, J=1.5 Hz, aromatic H), 6.96 (d, 2H, J=15.3 Hz, H-2, 6), 6.90 (d, 2H, J=8.1 Hz, aromatic ring H), 3.96 (s, 6H, OCH3), 3.94 (s, 6H, OCH3), 2.66-2.57 (m, 2H, —CH 2CH3), 1.24 (t, 2H, J=15.0, 6.0 Hz, —CH2CH 3).
- Compound Q103, yellow crystal from EtOAc, mp. 125-126° C. ESI MS m/z: 453.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.74-7.61 (2H, H-1, 7), 7.21-7.06 (m, 4H, aromatic H), 6.99-6.71 (4H, H-2, 6 and aromatic H), 3.94-3.92 (12H, —OCH3), 2.57 (t, 1H, H-4), 1.51-1.22 (m, 6H, —CH2CH2CH2—), 0.87 (3H, —CH3).
- Compound Q108, yellow solid from EtOAc, mp. 60-62° C. ESI MS m/z: 515.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.72-7.60 (2H, H-1, 7), 7.34-7.00 (m, 8H, aromatic H), 6.91-6.84 (3H, aromatic H), 6.82-6.68 (2H, H-2, 6), 3.95-3.92 (12H, —OCH3), 3.46 (t, 1H, H-4), 2.80-2.52 (m, 2H, benzyl CH 2), 2.12-1.84 (2H, —CH 2—), 1.68-1.50 (2H, —CHCH 2—).
- Compound JM12, orange needles from EtOAc/hexanes; mp. 138-139° C.; ESI MS m/z: 451.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.72, 6.99 (both d, 2H each, J=15.3 Hz, H-1, 2, 6, 7), 7.21 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.08 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.90 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.93 (both s, 6H each, OCH3), 2.65 (d, 2H, J=6.0 Hz, C4-CH2—), 0.95 (m, 1H, CH of cyclopropane), 0.95 (m, 1H, CH of cyclopropane), 0.51, 0.24 (both m, 2H each, CH2 of cyclopropane).
- Compound JM13, orange needles from EtOAc/hexanes; mp. 172-174° C.; ESI MS m/z: 493.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.71, 6.97 (both d, 2H each, J=15.3 Hz, H-1, 2, 6, 7), 7.20 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.08 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.94 (both s, 6H each, OCH3), 2.46 (d, 2H, J=6.9 Hz, C4-CH2—), 1.90-1.00 (m, 11H, 1 CH and 5 CH2 of cyclohexane).
- Compound JM14, orange needles from EtOAc/hexanes; mp. 131-132° C.; ESI MS m/z: 493.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 9.87 (br.s, 1H, OH), 7.76, 6.90 (both d, 2H each, J=15.3 Hz, H-1, 2, 6, 7), 7.19 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.10 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.91 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.30 (br. s, 1H, OH), 3.95, 3.94 (both s, 6H each, OCH3), 2.86, 2.37 (both m, 2H each, C4-CH2—CH2—).
- Compound JM16, orange amorphous; ESI MS m/z: 437.2 [M+H]+; 1H NMR (300 MHz, CDCl3, 2:1 tautomerism observed, data for major form listed) δ: 7.62, 6.71 (both d, 2H each, J=15.9 Hz, H-1, 2, 6, 7), 7.12 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.05 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 5.96 (br. s, 2H, OH×2), 3.97 (s, 3H, OCH3), 3.94 (s, 9H, OCH3×3), 2.68 (d, 2H, J=6.9 Hz, C4-CH2—), 2.19-1.59 (m, 7H, 1 CH and 3 CH2 of cyclobutane).
- Compound JM17, orange needle from EtOAc/hexanes, mp. 126-127° C.; ESI MS m/z: 465.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.72, 7.00 (both d, 2H each, J=15.3 Hz, H-1, 2, 6, 7), 7.21 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.09 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 3.96, 3.95 (both s, 6H each, OCH3), 2.70 (d, 2H, J=6.9 Hz, C4-CH2—), 2.08 (m, 2H, 1 CH2 of cyclobutane), 1.83 (m, 4H, 2 CH2 of cyclobutane).
- Compound JM18, orange amorphous; ESI MS m/z: 423.2 [M+H]+; 1H NMR (300 MHz, CDCl3, 2:1 tautomerism observed, data for major form listed) δ: 7.65, 6.73 (both d, 2H each, J=15.9 Hz, H-1, 2, 6, 7), 7.12 (dd, 2H, J=1.8, 8.4 Hz, aromatic 5′-H), 7.05 (d, 2H, J=1.8 Hz, aromatic 2′-H), 6.92 (d, 2H, J=8.4 Hz, aromatic 6′-H), 3.93 (s, 12H, OCH3×4), 2.71, 2.65 (both d, 1H each, J=6.0 Hz, C4-CH2—), 0.95 (m, 1H, CH of cyclopropane), 0.51, 0.24 (both m, 2H each, CH2 of cyclopropane).
- Compound JM19, orange reddish needle from EtOAc/hexanes; mp. 153-154° C.; ESI MS m/z: 465.2 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.75, 6.88 (both d, 2H each, J=15.5 Hz, H-1, 2, 6, 7), 7.17 (dd, 2H, J=1.6, 8.5 Hz, aromatic 5′-H), 7.07 (d, 2H, J=1.6 Hz, aromatic 2′-H), 6.96 (d, 2H, J=8.5 Hz, aromatic 6′-H), 5.90 (s, 2H, OH X 2), 3.96 (s, 6H, OCH3×2), 2.86, 2.35 (both m, 2H each, C4-CH2—CH2—).
- Compound Q114, yellow crystalline solid from EtOAc/hexanes, mp. 166-167° C. ESI MS m/z: 337.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.63 (d, 2H, J=16.1 Hz, H-1, 7), 7.53-7.50 (m, 4H, aromatic H), 6.94-6.91 (m, 4H, aromatic H), 6.50 (d, 2H, J=16.1 Hz, H-2, 6), 5.79 (s, 1H, H-4), 3.85 (s, 6H, OCH3).
- Compound Q115, yellow crystal from EtOAc, mp. 142-143° C. ESI MS m/z: 393.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.73 (d, 2H, J=15.6 Hz, H-1, 7), 7.55-7.52 (4H, aromatic H), 6.99-6.92 (6H, H-2, 6 and aromatic H), 3.86 (6H, —OCH3), 2.55 (t, 1H, H-4), 1.53-1.40 (m, 6H, —CH2CH2CH2—), 1.01 (t, 3H, —CH3).
- Synthesis of compounds: JM4, JM20, and Q116.
- Compounds JM4, JM20, Q116 structurally share the property of a (substituted)-triaryl system [three (substituted phenyl) propenal conjugation]. One of the purposes to synthesize these compounds is to study the effect of multi-phenyl propenal moiety on anti-AR and anti-prostate cancer activities. Compound JM4 were synthesized from a condensation of 3,4-dimethyoxybenzaldehyde with triacetylmethane as shown in
Scheme 11. - Compounds JM20 and Q116 were synthesized with the same method described as JM4.
- Compound JM20, red powder, mp. 165-167° C.; ESI MS m/z: 455.2 [M+H]+; 1H NMR (300 MHz, d6-DMSO) δ: 7.69 (d, 2H, J=15.6 Hz, H-1, 7), 7.03 (d, 1H, J=16.2 Hz, C4 side chain —COCH═CH—), 7.62-7.34 (m, 6H, aromatic ring H), 6.67 (d, 1H, J=15.6 Hz, C4 side chain —COCH═CH—), 6.90-6.72 (m, 4H, aromatic H), 6.57 (d, 2H, J=15.9 Hz, H-2, 6).
- Compound Q116, yellow amorphous solid, mp. 70-72° C. ESI MS m/z: 497.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.78 (d, 2H, J=15.3 Hz, H-1, 7), 7.60 (d, H, J=15.6 Hz, C4 side chain —COCH═CH—), 7.54-7.51 (2H, aromatic ring H), 7.47-7.44 (4H, aromatic ring H), 6.97 (d, 1H, J=15.6 Hz, C4 side chain —COCH═CH—), 6.92-6.85 (6H, aromatic H), 6.71 (d, 2H, J=15.3 Hz, H-2, 6), 3.84-3.82 (9H, —OCH3).
- Synthesis of compound: JM5.
- Compound JM5 structurally containing four (substituted phenyl) propenal moieties was synthesized by reaction of ASC-J9 (18.9 g) with bromomethyl acetate (10.0 g) in anhydrous acetone (250 mL) in the presence of sodium carbonate (5.0 g) (Scheme 12). After heating to reflux for 80 h, the solid was filtered and the filtrate was concentrated under vacuum. The residue was subjected repeated silica gel column chromatography (n-hexanes:ethyl acetate=2:1) to afford the desired product and recovered starting material ASC-J9 (15 g). The obtained product was dissolved in 0.5 mL of ethyl acetate and was added dropwise to 5 mL of hexanes with stirring. After filtration and drying in vacuum to give compound JM5 (877 mg) as a yellow powder. Compound JM5 was also synthesized by reaction of ASC-J9 with bromomethyl methyl ether and sodium carbonate in anhydrous acetone in shorter time and with higher yield.
- Analytical data on compound JM5 are shown below.
- Yellow amorphous. mp. 111-114° C. ESI MS m/z: 804.87 [M+H]+; 1H and 13C NMR data on 500 MHz Varian, (CDCl3) was listed in Table 1.
-
TABLE 1 1H and 13C NMR Spectral Data of ASC-JM5. No. Groups δ 1H δ 13C a1 Ar. ═C 126.83 a2 Ar. ═CH 7.098 (d, J = 1.5) 109.62 a3, 4, b3, 4, c3, Ar. ═C(OCH3) *3.812 (s), 3.596, 3.708, 3.968, 147.77, 147.93, 148.96, 149.15, c4, d3, 4. 3.950, 3.946, 3.857, 3.931 149.17, 151.25, 151.69, 151.87 a5 Ar. ═CH 6.878 (d, J = 8.0) 110.82 a6 Ar. ═CH 7.167 (dd, J = 8.0, 1.5) 123.31 a11 ═CH 7.732 (d, J = 15.5) 143.25 a12 ═CH 7.017 (d, J = 15.5) 116.46 a13 C═O 182.21 a14 —CH— 4.317 (s) 40.75 b1 Ar. ═C 127.84 b2 Ar. ═CH 6.881 (d, J = 2.0) 109.57 b5 Ar. ═CH 6.740 (d, J = 8.0) 110.71 b6 Ar. ═CH 7.061 (dd, J = 8.0, 2.0) 124.09 b11 ═CH 7.681 (d, J = 15.5) 145.83 b12 ═CH 6.739 (d, J = 15.5) 118.33 b13 C═O 196.29 c1 Ar. ═C 126.80 c2 Ar. ═CH 7.055 (d, J = 1.5) 109.80 c5 Ar. ═CH 6.878 (d, J = 8.5) 110.82 c6 Ar. ═CH 7.195 (dd, J = 8.5, 1.5) 123.84 c11 ═CH 7.60 (d, J = 15.5) 144.71 c12 ═CH 7.038 (d, J = 15.5) 119.03 c13 C═O 194.59 c14 —CH— 4.317 (d, J = 7.5) 40.69 d1 Ar. ═C 133.03 d2 Ar. ═CH 6.653 (s) 111.92 d5 Ar. ═CH 6.740 (d, J = 8.5) 110.71 d6 Ar. ═CH 6.676 (d, J = 8.0) 120.28 d11 —C— 68.86 d12 —CH2 3.268 (d, J = 16.5), 24.13 3.352 (d, J = 16.5) d13 C═O 190.32 d14 —CH2 2.734 (d, J = 19.5), 37.74 3.516 (dd, J = 19.5, 7.5) a3, 4, b3, 4, c3, —OCH3 3.596 (s), 55.40 c4, d3, 4. 3.708 (s), 3.812 (s), 55.59 3.857 (s), 3.946 (s), 55.87 3.931 (s), 3.950 (s), 55.94 3.968 (s) 56.05 *1 H data of the methoxy protons
Synthesis of compounds: Q110 and Q111. - In order to study the contribution of the length of the conjugation bridge to the AR activity, compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13. Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solution of 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated. The residue was dissolved in EtOAc and washed with water, 2% NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography and eluted with hexanes-ethyl acetate mixture to give a light yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P. Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of 2,4-petanedione (3 eq.) and B2O3 (1 eq.) in EtOAc was stirred at 40° C. for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1 eq.) were added. The resulting reaction mixture was stirred at 40° C. for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at the temperature and stirred at 40° C. for 16 h. To the red reaction mixture, 1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. After cooling to rt, the aqueous was separated and the organic was washed with water to pH˜7 and dried over Na2SO4. The crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid. A solution of the intermediate (1 eq.) and B2O3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C. for 1 h. After cooling to 60° C., 1% HCl aq was added and the mixture was stirred at 60° C. for 0.5 h. The reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Q110 as a red solid. Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring H and trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48 (1H, trans double bond H), 6.18-6.12 (1H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3).
- Compound Q111 was synthesized by reaction of 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one (3) with 3,4-dimethoxycinnamaldehyde (2) as described in the synthesis of Q110 (Scheme 13). A red amorphous solid was afforded, mp. 187-9° C. ESI MS m/z: 449.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.49-7.40 (d, 2H, H-1 and 11), 7.06-7.02 (4H, aromatic ring H), 6.87-6.81 (2H, aromatic ring H, and 4H for trans double bond H), 6.17-6.12 (2H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3).
- Representative ASC compounds and monomers were tested for their activity to block androgen/AR-induced functions. A cell growth assay using human prostate cancer cells, either LNCaP or CWR22Rv1, was applied in the studies. Functional AR proteins are expressed in both cancer cell lines; whereas the growth of LNCaP cells is DHT dependant, but the growth of CWR22Rv1 cells, derived from a relapsed hormone-refractory tumor, was not. In addition, Western Blot analysis were performed by testing monomers, and some representative new compounds in prostate cancer cells to demonstrate that compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing AR protein expression levels and inhibiting cancer cell growth in vitro.
- The MTT cell proliferation assay was applied in the present invention to detect the capability of compounds to suppress or inhibit prostate cancer cells growth. The MTT assay, which is a method widely used to detect proliferation of culture cells and is relied upon the conversion of a colorless substrate to reduced tetrazolium by a mitochondrial dehydrogenase (possessed by all viable cells), and has been demonstrated previously (Su et al., 1999) to assess the growth of various tissue-cultured cells. Briefly, 1×103 LNCaP or CWR22Rv1 cells suspended in complete medium were plated into each well of a 96-well Microtest III tissue culture plate (Falcon, N.J.). Two days later, the medium was replaced with RPMI-1640 medium containing 10% charcoal/dextran-deprived FBS (hormone-deprived fetal bovine serum). Testing compounds were added to the medium at indicated concentrations with or without 1 nM DHT and cells were cultured for 5 days in an incubator (at 37° C.). MTT substrate solution (5 mg/ml in PBS) in 1/10 of volume was added to the cells in each well at 2 hours before harvesting. After 2 hour incubation, the plates were centrifuged (10 min at 1,000 rpm) and the supernatant from each well was carefully removed. A 100 μl of lysis buffer (50% dimethyl formamide, 5% sodium dodecyl sulphate, 0.35 M acetic acid, and 50 mM HCl) was added to each well to lyse the cells and dissolved tetrazolium in each well. The relative quantity of enzyme activity from each well was measured based on absorbance read at a wavelength of 450 nm using a Bio-RAD BenchMark microplate reader. Data derived from the MTT assay were also verified by the actual cell count and cell morphology on a separate plate set up in parallel. Data from this parallel plate demonstrated a positive relationship between the quantity of enzyme activity and the number of viable cells in the well.
- A widely used Western Blotting analysis was employed to measure AR protein expression level. Human prostate cancer cells, LNCaP and CWR22Rv1, both express high levels of AR proteins and were used in this study. In this invention representative ASC compounds were tested in Western blot assay to evaluate their activity in reducing AR expression; and the assays were carried out in either the presence or absence of dihydrotestosterone (DHT, 1 nM). After cells were incubated with testing compounds for the designated time, they were harvested and lysed according to Western Blot techniques known in the biochemical arts. Details of Western Blotting analysis method have been published previously (Su et al., 1999). Briefly, cells were harvested either in 2× sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS/PAGE) loading buffer or in Radio-Immunoprecipitation Assay (RIPA) lysis buffer strengthened with 10 μg/ml of benzamidine, 10 μg/ml of trypsin inhibitor, and 1 mM of phenylmethylsulfonyl fluoride. A sample of total protein (approximately 40 μg) from each cell lysate was separated by electrophoresis on a SDS/PAGE gel. After separation by electrophoresis, the proteins were transferred from the gel to a nitrocellulose membrane following the standard procedures. The membrane was then incubated with 10% non-fat milk in phosphate-buffered saline supplemented with 0.1% Tween-20 (PBST) for 1 hour and then followed with an overnight incubation with a primary human AR-specific antibody (purchased from BD-PharMingen) at 4° C. After incubation, the membrane was rinsed with PBST buffer three times; 10 min each time; an alkaline phosphatase-conjugated secondary antibody was then added and incubated for 1 hour at room temperature. After second antibody incubation, membrane was again rinsed with PBST, and AR protein signal in the membrane was visualized by adding alkaline phosphatase substrates, bromochloroindolyl phosphate and nitro blue tetrazolium to the membrane. To assure that an equal amount of protein from each sample was analyzed, a portion of the membrane was stained with a specific antibody for a house keeping protein β-actin (Santa Cruz Biotechnology) and actin signal was revealed with a second antibody as described above. The protein signal intensity (shown as colour band on the membrane) was measured using densitometer and analysed by using NIH Image J software (NIH 1.33). The quantity of AR protein was calculated by normalizing the quantity of AR to the quantity of β-actin in each sample and data are expressed in relative quantity.
- AR protein “degradation” in prostate cancer cells was measured by using cycloheximide (a protein synthesis inhibitor) chasing assay method. Briefly, LNCaP cells were incubated with testing ASC compound at the designated concentrations for 24 hours. Subsequently, cycloheximide was added to the cells at a concentration of 15 μg/ml to block new protein synthesis. After incubation, cells were harvested at designated time periods and the resultant change in AR protein levels were analysed using Western Blot analysis as described above.
Claims (33)
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/008,124 US8236852B2 (en) | 2007-01-08 | 2008-01-08 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US12/800,251 US8202905B2 (en) | 2007-01-08 | 2010-05-11 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US13/525,941 US8710272B2 (en) | 2007-01-08 | 2012-06-18 | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US13/920,199 US9000222B2 (en) | 2007-01-08 | 2013-06-18 | Compounds with (1E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US14/622,883 US9259402B2 (en) | 2007-01-08 | 2015-02-15 | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyI)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US15/044,685 US9562025B2 (en) | 2007-01-08 | 2016-02-16 | Compounds with (1E, 6E)-1,7-Bis-(3,4-dimethoxyphenyl)-4-4-distributed-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US87945807P | 2007-01-08 | 2007-01-08 | |
US12/008,124 US8236852B2 (en) | 2007-01-08 | 2008-01-08 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/008,124 Continuation-In-Part US8236852B2 (en) | 2007-01-08 | 2008-01-08 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US12/800,251 Continuation-In-Part US8202905B2 (en) | 2007-01-08 | 2010-05-11 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US14/622,883 Continuation US9259402B2 (en) | 2007-01-08 | 2015-02-15 | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyI)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/008,124 Continuation-In-Part US8236852B2 (en) | 2007-01-08 | 2008-01-08 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US12/800,251 Division US8202905B2 (en) | 2007-01-08 | 2010-05-11 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US13/525,941 Continuation-In-Part US8710272B2 (en) | 2007-01-08 | 2012-06-18 | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
US20080188557A1 true US20080188557A1 (en) | 2008-08-07 |
US8236852B2 US8236852B2 (en) | 2012-08-07 |
Family
ID=39609007
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/008,124 Active 2029-06-10 US8236852B2 (en) | 2007-01-08 | 2008-01-08 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
US12/800,251 Active 2028-03-29 US8202905B2 (en) | 2007-01-08 | 2010-05-11 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/800,251 Active 2028-03-29 US8202905B2 (en) | 2007-01-08 | 2010-05-11 | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
Country Status (12)
Country | Link |
---|---|
US (2) | US8236852B2 (en) |
EP (2) | EP2104659B1 (en) |
JP (3) | JP2010515685A (en) |
KR (1) | KR101563370B1 (en) |
CN (1) | CN101711231B (en) |
AU (1) | AU2008205312B2 (en) |
CA (1) | CA2674780C (en) |
DK (1) | DK2104659T3 (en) |
HK (2) | HK1143802A1 (en) |
MX (1) | MX2009007345A (en) |
NZ (1) | NZ578914A (en) |
WO (1) | WO2008085984A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI703975B (en) * | 2018-03-23 | 2020-09-11 | 美力齡生醫股份有限公司 | Uses of curcumin derivative |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ578914A (en) * | 2007-01-08 | 2012-11-30 | Andhoscience Corp | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and uses thereof |
US8710272B2 (en) | 2007-01-08 | 2014-04-29 | Androscience Corporation | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US9000222B2 (en) | 2007-01-08 | 2015-04-07 | Androscience Corporation | Compounds with (1E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US20110036771A1 (en) | 2007-01-09 | 2011-02-17 | Steven Woodard | Ballasted anaerobic system and method for treating wastewater |
CA2694953C (en) * | 2007-07-31 | 2015-12-01 | Androscience Corporation | Compositions including androgen receptor degradation (ard) enhancers and methods of prophylactic or therapeutic treatment of skin disorders and hair loss |
US9150860B2 (en) | 2008-07-22 | 2015-10-06 | The General Hospital Corporation | FUS/TLS-based compounds and methods for diagnosis, treatment and prevention of amyotrophic lateral sclerosis and related motor neuron diseases |
CN101700995B (en) * | 2008-12-30 | 2013-06-05 | 中山大学 | Polyvinylarene substituted beta-diketones with anti-tumor effects |
US9187406B2 (en) | 2009-05-15 | 2015-11-17 | The Research Foundation Of State University Of New York | Curcumin analogues as zinc chelators and their uses |
LT2486026T (en) * | 2009-10-09 | 2020-09-10 | Alexander Macgregor | Derivatives of di(phenylpropanoid) glycerol for the treatment of cancer |
US8822732B2 (en) * | 2010-08-20 | 2014-09-02 | Androscience Corporation | 1,5-diphenyl-penta-1,4-dien-3-one compounds |
CN102060795B (en) * | 2011-01-14 | 2012-01-25 | 扬州大学 | Method for synthesizing 1,3,5-triphenyltriazine |
HUP1100532A2 (en) | 2011-09-23 | 2013-04-29 | Avidin Kft | Substituted curcumin derivatives, process for their preparation, and pharmaceutical compositions containing them |
KR102171469B1 (en) * | 2012-06-18 | 2020-10-30 | 알리안츠 파마사이언스 리미티드 | Compounds with (1e,6e)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof |
US9220695B2 (en) | 2012-06-29 | 2015-12-29 | The Research Foundation For The State University Of New York | Polyenolic zinc-binding agents (pezbins) actively promote inactivation of cancer stem cells and potentiate cytotoxic anti-tumor drug substances |
US9371263B2 (en) * | 2013-09-20 | 2016-06-21 | Augusta University Research Institute, Inc. | Protective effects of curcumin against hemorrhagic stroke injury |
US10300000B2 (en) | 2016-09-12 | 2019-05-28 | The Research Foundation For The State University Of New York | Inhibition of melanogenesis by chemically modified curcumins |
WO2019084365A1 (en) * | 2017-10-27 | 2019-05-02 | St. Jude Children's Research Hospital, Inc. | Methods and formulations for treatment of spinobulbar muscular atrophy |
EP3508855A1 (en) * | 2018-01-05 | 2019-07-10 | Allianz Pharmascience Ltd | Method for the selection of patients and kit |
JP2020117488A (en) * | 2019-01-04 | 2020-08-06 | アリアンツ ファーマサイエンス リミテッド | Method for treating inflammatory disorder |
CN110183320B (en) * | 2019-04-15 | 2021-06-11 | 四川大学 | Polyene diketone antitumor compound |
Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4806683A (en) * | 1986-02-28 | 1989-02-21 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of cinnamic acids |
US5334481A (en) * | 1985-05-02 | 1994-08-02 | Ciba-Geigy Corporation | Positive diazo quinone photoresist compositions containing antihalation compound |
US5496556A (en) * | 1990-06-27 | 1996-03-05 | Smithkline Beecham Corporation | Method of treating prostatic adenocarcinoma |
US5609858A (en) * | 1994-11-22 | 1997-03-11 | Buck; Carol J. | Method for treatment of androgenic alopecia |
US5637310A (en) * | 1993-12-20 | 1997-06-10 | Smithkline Beecham Corporation | Method of treating prostatic adenocarcinoma |
US5733886A (en) * | 1992-02-18 | 1998-03-31 | Lloyd J. Baroody | Compositions of clindamycin and benzoyl peroxide for acne treatment |
US5883124A (en) * | 1991-10-21 | 1999-03-16 | The United States Of America As Represented By The Department Of Health And Human Services | Compositions and methods for treating and preventing pathologies including cancer |
US5958645A (en) * | 1996-08-28 | 1999-09-28 | Japan Synthetic Rubber Co., Ltd. | Radiation-sensitive resin composition |
US6218369B1 (en) * | 1995-05-23 | 2001-04-17 | Indena S.P.A. | Pharmaceutical compositions containing flavanolignanes and methods for using same as an antiproliferative |
US20030198990A1 (en) * | 1998-07-17 | 2003-10-23 | Chawnshang Chang | Androgen receptor coactivators |
US20030203933A1 (en) * | 2002-04-17 | 2003-10-30 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
US20050187255A1 (en) * | 2002-04-17 | 2005-08-25 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
US20060024385A1 (en) * | 2004-07-27 | 2006-02-02 | Pedersen Mark A | Metabolic capacity enhancing compositions and methods for use in a mammal |
US20060199768A1 (en) * | 2005-03-07 | 2006-09-07 | University Of North Carolina At Chapel Hill | Inhibitors of RecA activities for control of antibiotic-resistant bacterial pathogens |
US20060258752A1 (en) * | 2004-02-12 | 2006-11-16 | Vander Jagt David L | Method and compounds for cancer treatment utilizing NFkB as a direct or ultimate target for small molecule inhibitors |
US20060275516A1 (en) * | 2005-06-02 | 2006-12-07 | Ram A N S | Compositions and methods for the treatment of allergic rhinitis |
US20070204412A1 (en) * | 2006-03-01 | 2007-09-06 | Gelest, Inc. | Curcumin and its derivatives for use as silicone colorants |
US20080103213A1 (en) * | 2004-03-05 | 2008-05-01 | Board Of Regents, The University Of Texas System | Liposomal curcumin for treatment of neurofibromatosis |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2728242A1 (en) * | 1977-06-23 | 1979-01-11 | Henkel Kgaa | COSMETIC LIGHT PROTECTION AGENTS FOR THE UV-A AREA |
GR79447B (en) | 1982-12-31 | 1984-10-30 | Mortimer Christopher H Dr | |
JPS6032756A (en) * | 1983-08-02 | 1985-02-19 | Nippon Redarii Kk | Production of n-(cis-3,4-dimethoxycinnamoyl)-anthranylic acid |
US4649157A (en) * | 1986-03-28 | 1987-03-10 | G. D. Searle & Co. | Pharmaceutical compositions containing 5-phenyl-1,3-dioxoalkenyl compounds |
JPH0390021A (en) * | 1989-09-01 | 1991-04-16 | Terumo Corp | Medicine preparation containing zingerol derivative |
IT1255467B (en) * | 1992-07-29 | 1995-11-02 | Dompe Farmaceutici Spa | PHARMACOLOGICALLY ACTIVE ACRYLIC STARCHES |
US5679864A (en) * | 1995-11-03 | 1997-10-21 | Gene Print Inc. | Process for the synthesis of curcumin-related compounds |
AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
JP2000258904A (en) * | 1999-03-04 | 2000-09-22 | Fujifilm Olin Co Ltd | Negative chemically amplified photosensitive composition |
JP2000256259A (en) * | 1999-03-11 | 2000-09-19 | Nippon Zoki Pharmaceut Co Ltd | Maillard reaction-inhibiting agent |
FR2799753B1 (en) * | 1999-10-19 | 2002-01-04 | Atofina | IMPROVED PROCESS FOR THE MANUFACTURE OF SYMMETRIC ANHYDRIDES |
TWI290469B (en) * | 2000-07-12 | 2007-12-01 | Medical & Pharm Ind Tech & Dev | Method for manufacturing product with component capable of efficiently preventing inflammation and platelets agglutination form ginger and medical composition with the efficient component |
JP4596441B2 (en) | 2000-08-22 | 2010-12-08 | 有限会社吉川塩ビ工業所 | Mixed fluid separator |
WO2003011280A1 (en) | 2001-07-27 | 2003-02-13 | University Of Rochester | Use of vitamin e succinate and antiandrogen combination |
JP2003073392A (en) * | 2001-09-04 | 2003-03-12 | Univ Nihon | Novel cinnamic acid derivative, composition including the same, antiallergic and anti-inflammatory agent |
WO2004080396A2 (en) * | 2003-03-07 | 2004-09-23 | The University Of Texas Md Anderson Cancer Center | Liposomal curcumin for treatment of cancer |
TWI287990B (en) | 2004-01-08 | 2007-10-11 | Nat Defense Medical Ct | Inhibitors and enhancers of uridine diphosphate-glucuronosyl transferase 2B (UGT2B) |
EP1765346A4 (en) | 2004-01-28 | 2008-10-15 | Androscience Corp | Enhancement of anti-androgenic activity by a combination of inhibitors targeting different steps of a steroid-dependent gene activation pathway and uses thereof |
US20060004875A1 (en) * | 2004-05-11 | 2006-01-05 | Microsoft Corporation | CMDB schema |
EP1804806A2 (en) | 2004-09-02 | 2007-07-11 | AndroScience Corporation | Methods and compositions for enhancing degradation of nuclear receptor transcription factors and uses thereof |
AU2006330769A1 (en) | 2005-12-29 | 2007-07-05 | Kansas State University Research Foundation | Antimicrobial cathelicidin peptides |
NZ578914A (en) * | 2007-01-08 | 2012-11-30 | Andhoscience Corp | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and uses thereof |
-
2008
- 2008-01-08 NZ NZ578914A patent/NZ578914A/en unknown
- 2008-01-08 WO PCT/US2008/000285 patent/WO2008085984A1/en active Application Filing
- 2008-01-08 EP EP08713067.0A patent/EP2104659B1/en active Active
- 2008-01-08 JP JP2009544955A patent/JP2010515685A/en active Pending
- 2008-01-08 CA CA2674780A patent/CA2674780C/en active Active
- 2008-01-08 AU AU2008205312A patent/AU2008205312B2/en active Active
- 2008-01-08 DK DK08713067.0T patent/DK2104659T3/en active
- 2008-01-08 EP EP15178708.2A patent/EP2993165B1/en not_active Not-in-force
- 2008-01-08 CN CN200880005067.7A patent/CN101711231B/en active Active
- 2008-01-08 KR KR1020097016216A patent/KR101563370B1/en active IP Right Grant
- 2008-01-08 US US12/008,124 patent/US8236852B2/en active Active
- 2008-01-08 MX MX2009007345A patent/MX2009007345A/en unknown
-
2010
- 2010-05-11 US US12/800,251 patent/US8202905B2/en active Active
- 2010-10-28 HK HK10110115.7A patent/HK1143802A1/en unknown
-
2013
- 2013-09-19 JP JP2013194113A patent/JP5998117B2/en active Active
-
2015
- 2015-10-29 JP JP2015212420A patent/JP2016065068A/en active Pending
-
2016
- 2016-09-01 HK HK16110440.7A patent/HK1222168A1/en not_active IP Right Cessation
Patent Citations (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5334481A (en) * | 1985-05-02 | 1994-08-02 | Ciba-Geigy Corporation | Positive diazo quinone photoresist compositions containing antihalation compound |
US5399463A (en) * | 1985-05-02 | 1995-03-21 | Ciba-Geigy Corporation | Process of photopatterning a substrate with a positive photoresist composition containing a diazoquinone photosensitizer |
US4806683A (en) * | 1986-02-28 | 1989-02-21 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of cinnamic acids |
US5496556A (en) * | 1990-06-27 | 1996-03-05 | Smithkline Beecham Corporation | Method of treating prostatic adenocarcinoma |
US5883124A (en) * | 1991-10-21 | 1999-03-16 | The United States Of America As Represented By The Department Of Health And Human Services | Compositions and methods for treating and preventing pathologies including cancer |
US5733886A (en) * | 1992-02-18 | 1998-03-31 | Lloyd J. Baroody | Compositions of clindamycin and benzoyl peroxide for acne treatment |
US5637310A (en) * | 1993-12-20 | 1997-06-10 | Smithkline Beecham Corporation | Method of treating prostatic adenocarcinoma |
US5609858A (en) * | 1994-11-22 | 1997-03-11 | Buck; Carol J. | Method for treatment of androgenic alopecia |
US6218369B1 (en) * | 1995-05-23 | 2001-04-17 | Indena S.P.A. | Pharmaceutical compositions containing flavanolignanes and methods for using same as an antiproliferative |
US5958645A (en) * | 1996-08-28 | 1999-09-28 | Japan Synthetic Rubber Co., Ltd. | Radiation-sensitive resin composition |
US20030198990A1 (en) * | 1998-07-17 | 2003-10-23 | Chawnshang Chang | Androgen receptor coactivators |
US20030203933A1 (en) * | 2002-04-17 | 2003-10-30 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
US6790979B2 (en) * | 2002-04-17 | 2004-09-14 | University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
US20050187255A1 (en) * | 2002-04-17 | 2005-08-25 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
US7355081B2 (en) * | 2002-04-17 | 2008-04-08 | The University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
US20060258752A1 (en) * | 2004-02-12 | 2006-11-16 | Vander Jagt David L | Method and compounds for cancer treatment utilizing NFkB as a direct or ultimate target for small molecule inhibitors |
US20080103213A1 (en) * | 2004-03-05 | 2008-05-01 | Board Of Regents, The University Of Texas System | Liposomal curcumin for treatment of neurofibromatosis |
US20060024385A1 (en) * | 2004-07-27 | 2006-02-02 | Pedersen Mark A | Metabolic capacity enhancing compositions and methods for use in a mammal |
US20060199768A1 (en) * | 2005-03-07 | 2006-09-07 | University Of North Carolina At Chapel Hill | Inhibitors of RecA activities for control of antibiotic-resistant bacterial pathogens |
US20060275516A1 (en) * | 2005-06-02 | 2006-12-07 | Ram A N S | Compositions and methods for the treatment of allergic rhinitis |
US20070204412A1 (en) * | 2006-03-01 | 2007-09-06 | Gelest, Inc. | Curcumin and its derivatives for use as silicone colorants |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI703975B (en) * | 2018-03-23 | 2020-09-11 | 美力齡生醫股份有限公司 | Uses of curcumin derivative |
US11135185B2 (en) | 2018-03-23 | 2021-10-05 | Merry Life Biomedical Company, Ltd. | Uses of curcumin derivative |
Also Published As
Publication number | Publication date |
---|---|
US8236852B2 (en) | 2012-08-07 |
AU2008205312B2 (en) | 2013-11-21 |
EP2104659B1 (en) | 2015-07-29 |
KR20090114387A (en) | 2009-11-03 |
HK1143802A1 (en) | 2011-02-25 |
EP2993165A3 (en) | 2016-07-06 |
JP2010515685A (en) | 2010-05-13 |
DK2104659T3 (en) | 2015-11-02 |
EP2993165B1 (en) | 2018-06-27 |
US8202905B2 (en) | 2012-06-19 |
NZ578914A (en) | 2012-11-30 |
US20100292342A1 (en) | 2010-11-18 |
JP5998117B2 (en) | 2016-09-28 |
WO2008085984A1 (en) | 2008-07-17 |
HK1222168A1 (en) | 2017-06-23 |
CN101711231B (en) | 2014-03-12 |
CA2674780C (en) | 2014-03-11 |
MX2009007345A (en) | 2010-02-22 |
EP2104659A1 (en) | 2009-09-30 |
EP2993165A2 (en) | 2016-03-09 |
KR101563370B1 (en) | 2015-10-26 |
CN101711231A (en) | 2010-05-19 |
JP2014055134A (en) | 2014-03-27 |
AU2008205312A1 (en) | 2008-07-17 |
CA2674780A1 (en) | 2008-07-17 |
EP2104659A4 (en) | 2011-09-07 |
JP2016065068A (en) | 2016-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8236852B2 (en) | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof | |
EP3150203B1 (en) | Compounds with (1e,6e)-1,7-bis-(3,4- dimethoxyphenyl)-4,4-disstituted-hepa-1,6-diene-3,5-di-one structural scaffold,their biological activity, and uses thereof | |
US7589123B2 (en) | Chemical compounds | |
US8710272B2 (en) | Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof | |
US9562025B2 (en) | Compounds with (1E, 6E)-1,7-Bis-(3,4-dimethoxyphenyl)-4-4-distributed-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof | |
TW201018458A (en) | Compound with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ANDROSCIENCE CORPORATION, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SHIH, CHARLES C.Y;SHIH, QIAN;WANG, HUI-KANG;AND OTHERS;REEL/FRAME:021036/0096 Effective date: 20080522 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
AS | Assignment |
Owner name: ALLIANZ PHARMASCIENCE LTD., TAIWAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ANDROSCIENCE CORPORATION;REEL/FRAME:036926/0822 Effective date: 20151020 |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 8 |
|
AS | Assignment |
Owner name: ANNJI PHARMACEUTICAL CO., LTD., TAIWAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALLIANZ PHARMASCIENCE LTD.;REEL/FRAME:058153/0317 Effective date: 20201229 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2553); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 12 |